This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cell proliferation-related disorders, cell death and apoptosis-related disorders.
Identification of therapeutic agents effective in the treatment of neoplastic diseases or for the treatment of neurological disorders is the subject of significant research efforts.
Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial list of such kinases includes ab1, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. As such, inhibition of kinases has become an important therapeutic target.
Cell proliferation is the rapid reproduction of cells, such as by cell division The cell cycle, which controls cell proliferation, is itself controlled by a family of serine-threonine kinases called cyclin dependent kinases (CDKs). The regulation of CDK activation is complex, and requires the association of the CDK with a member of the cyclin family of regulatory subunits. A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. Loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (T. Noguchi et al., Am. J. Pathol., 156, 2135-47 (2000)) As such, inhibition of CDKs has become an important target in the study of chemotherapeutics (A. Senderowicz and E. Sausville, J. Nat. Canc. Instit., 92, 376-87 (2000))
Kinases have also been implicated in diseases and disorders of the central nervous system. For example, patients suffering from stroke, Alzheimer""s disease or Parkinson""s disease would benefit from the inhibition of kinases. Cdk5 has been shown to be involved in Alzheimer""s pathology (R. Maccioni, et al., Eur. J. Biochem., 268, 1518-27 (2001)) and with neuronal development (G. Paglini and A. Caceres, Eur. J. Biochem., 268, 1528-33 (2001)).
Protein kinases also control programmed cell death, also known as apoptosis. Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. Disregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, inhibition of apoptosis has become an important therapeutic target. Cdk5 has been shown to be involved in apoptosis pathology (A. Catania et al., Neuro-Oncology, 89-98 (April 2001)).
Substituted heterocyclic compounds are known in the pesticide art. WO00/24735, published May 4, 2000, describes 1-pyridyl-1,2,4-triazoles as pesticides. WO00/24739, published May 4, 2000, describes substituted 1,2,4-triazoles as pesticides. WO97/01552, published Jan. 16, 1997, describes substituted 1,2,4-triazoles as antifungal agents. DE4204492 describes substituted benzamides as pesticides. WO98/57969, published Dec. 23, 1998, describes heterocyclylpyridines as pesticides. GB2293380, published Mar. 27, 1996, describes the use of heterocyclic compounds as pesticides. U.S. Pat. No. 5,693,667, issued Dec. 2, 1997, describes heterocyclic compounds for the treatment of take-all disease. EP468695 describes fungicide compounds. U.S. Pat. No. 5,294,596, issued Mar. 15, 1994, describes herbicidal triazolinones. U.S. Pat. No. 5,395,818, issued Mar. 7, 1995, describes herbicidal triazolinones.
Substituted thiazoles also are known in the pesticide art. U.S. Pat. No. 4,260,765, issued Apr. 7, 1981, describes 2-(3-pyridyl)-5-thiazolecarboxamides for the treatment of aphids. U.S. Pat. No. 5,945,380, issued Aug. 31, 1999, describes 4-(4-pyridyl)pyrazoles as insecticides. WO89/00568, published Jan. 26, 1989, describes nicotine derivatives as fungicides.
Heterocyclic ureas are known in the pharmaceutical art. WO99/23091, published May 14, 1999, describes heterocyclic compounds as anti-inflammatories. WO99/32455, published Jul. 1, 1999, describes heterocyclic ureas as RAF kinase inhibitors. WO99/32110, published Jul. 1, 1999, describes heterocyclic ureas as p38 kinase inhibitors. WO99/32106, published Jul. 1, 1999, describes heterocyclic ureas as RAF kinase inhibitors. WO99/32111, published Jul. 1, 1999, describes heterocyclic ureas as p38 kinase inhibitors. WO99/32436, published Jul. 1, 1999, describes urea compounds as inhibitors of RAF kinase. WO99/32463, published Jul. 1, 1999, describes urea compounds that inhibit p38 kinase. WO98/52558, published Nov. 26, 1998, describes urea compounds for the inhibition of p38 kinase. WO99/00357, published Jan. 7, 1999, describes the use of urea compounds as inhibitors of p38 kinase. WO99/58502, published Nov. 18, 1999, describes urea compounds as inhibitors of p38 kinase. U.S. Pat. No. 5,821,245, issued Oct. 13, 1998, describes substituted naphthalene derivatives for treating cell growth. GB patent 1,437,895 describes 2-thiazolyl ureas for the treatment of ulcers. U.S. Pat. No. 5,364,871, issued Nov. 15, 1994 describes thiazoles as anti-ulcer compounds. WO99/21555, published May 6, 1999, describes pyridyl-substituted thiazoles as adenosine A3 receptor antagonists. WO96/23783 describes indole derivatives as 5-HT receptor antagonists. U.S. Pat. No. 5,208,248 describes indazole derivatives as 5-HT receptor antagonists. WO99/46244, published Sep. 16, 1999 describes heterocyclic compounds as tyrosine phosphatases. GB patent 2,263,109, published Jul. 14, 1993, describes pyridylthiazoles as PAF-receptor antagonists.
Thiazole compounds have also been described as inhibitors of CDK. WO00/26203, published May 11, 2000, describes 2-ureidothiazoles as inhibitors of cdk. WO99/65884 describes 2-aminothiazoles as inhibitors of CDK. WO99/24416 describes 2-aminothiazoles as inhibitors of CDK.
However, compounds of the current invention have not been described as inhibitors of cell proliferation or apoptosis such as for the treatment of cancer or stroke.
A class of compounds useful in treating cell proliferative disorders, neurological disorders and apoptosis is defined by Formula I 
wherein each of A1-A6 is selected from CH2, CH, C, O, S, NH and N; wherein A1-A6 together form a ring A selected from
a) additionally substituted or unsubstituted 5- or 6-membered heterocyclyl,
preferably 5- or 6-membered heteroaryl,
more preferably 5-membered heteroaryl selected from thiazolyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, and
6-membered heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,
even more preferably 5-membered heteroaryl selected from thiazolyl, oxazolyl and imidazolyl, and 6-membered heteroaryl selected from pyridyl, and pyrimidinyl,
b) additionally substituted or unsubstituted 5- or 6-membered heteroaryl fused with a phenyl group,
c) additionally substituted or unsubstituted 5- or 6-membered cycloalkenyl,
preferably 5-membered cycloalkenyl,
more preferably cyclopentadienyl or cyclopentenyl, and
d) additionally substituted or unsubstituted phenyl,
wherein A is additionally substituted with one or more substituents independently selected from halo, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94CO2R3, xe2x80x94CO2NR3R3, xe2x80x94COR3, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94NR3C(O)OR3, xe2x80x94NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lower haloalkyl,
preferably one or more substituents independently selected from halo, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94CO2R3, xe2x80x94CO2NR3R3, xe2x80x94COR3, xe2x80x94NR3R3, xe2x80x94SO2NR3R3xe2x80x94NR3C(O)OR3, xe2x80x94NR3C(O)R3, C1-C2 alkyl, cyano, C1-C2 hydroxyalkyl, nitro, C2-C3 alkenyl, C2-C3 alkynyl and C1-C2 haloalkyl,
more preferably one or more substituents independently selected from fluoro, hydroxy, methoxy, amino and methyl;
wherein X and Z taken together form a nitrogen containing ring selected from
unsubstituted 5-6 membered heterocyclyl,
unsubstituted 5-6 membered heterocyclyl fused with a phenyl group,
5-6 membered heterocyclyl substituted with one or more substituents independently selected from R1, and
5-6 membered nitrogen-containing heterocyclyl, fused with a phenyl group, substituted with one or more substituents independently selected from R1,
preferably a ring selected from substituted or unsubstituted 5- or 6-membered nitrogen-containing heteroaryl, and substituted or unsubstituted 5- or 6-membered nitrogen-containing heteroaryl fused with a phenyl group,
more preferably substituted or unsubstituted thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoindolyl, indolyl, indazolyl, purinyl, [1,6]naphthyridinyl, 5,6,7,8-tetrahydro[1,6]naphthyridinyl, isoquinolyl and quinolyl,
even more preferably pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, [1,6]naphthyridinyl and 5,6,7,8-tetrahydro[1,6]naphthyridinyl,
most preferably pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,
most preferred pyridyl;
wherein R1 is independently selected from H, halo, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94CO2R3, xe2x80x94CO2NR3R3, xe2x80x94COR3, xe2x80x94CONR3R3, xe2x80x94NR3R3, xe2x80x94C(S)NR3R3, xe2x80x94SO2NR3R3, xe2x80x94NR3C(O)OR3, xe2x80x94NR3C(O)R3 cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, optionally substituted phenyl, optionally substituted phenoxy, lower alkyl, lower cyano, lower alkenyl, lower alkynyl and lower haloalkyl,
preferably optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, optionally substituted pyridyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, optionally substituted phenyl, C1-C4 alkyl, C1-C2 haloalkyl, halo, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, hydroxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, amino-C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, (optionally substituted pyrrolidinyl)-C1-C2alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, 4-morpholinyl-C1-C2-alkyl, (optionally substituted imidazolyl)-C1-C2-alkyl, phthalimidylethyl, optionally substituted azepanyl-C1-C2-alkyl, 1,4-dioxa-8-aza-spiro[4.5]decyl-C1-C2-alkyl, optionally substituted pyridyloxy, optionally substituted phenoxy, tetrahydrofuryl-O-, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted phenoxy-C1-C2-alkyl, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, tetrahydrofuryl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4alkoxy morpholinyl-C1-C4-alkylenylaminocarbonyl, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, aminocarbonyl, C1-C3-alkylaminothiocarbonyl, C1-C4-alkylamino and C1-C4-alkylamino-C1-C4-alkylamino,
more preferably 3-(N,N-dimethylamino)-1-pyrrolidinyl, 1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl, 1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl, 1-ethyl-4-piperazinyl, piperidinyl, morpholinyl, 4-amino-1-piperidinyl, 4-(N-hydroxyethylamino)-1-piperidinyl, 4-(N-propylamino)-1-piperidinyl, 4-(N-benzylamino)-1-piperidinyl, 4-oxo-piperidinyl, 4-(hydroxyimino)-piperidinyl, 4-morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amino, azidomethyl, hydroxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, fluoro, chloro, bromo, aminoethyl, aminomethyl, cyanomethyl, 1-pyrrolidinyl-CH2xe2x80x94, 2-methoxycarbonyl-1-pyrrolidinyl-CH2xe2x80x94, 2-carboxy-1-pyrrolidinyl-CH2xe2x80x94, 2-hydroxymethyl-1-pyrrolidinyl-CH2xe2x80x94, 1-piperidinyl-CH2xe2x80x94, 4-methyl-1-piperidinyl-CH2xe2x80x94, 3-methyl-1-piperidinyl-CH2xe2x80x94, 2-methyl-1-piperidinyl-CH2xe2x80x94, 3,5-dimethyl-1-piperidinyl-CH2xe2x80x94, 4-oxo-1-piperidinyl-CH2xe2x80x94, 4-hydroxy-1-piperidinyl-CH2xe2x80x94, 3-hydroxy-1-piperidinyl-CH2xe2x80x94, 2-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-carboxy-1-piperidinyl-CH2xe2x80x94, 4-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 4-carboxy-1-piperidinyl-CH2xe2x80x94, 4-(1-pyrrolidinyl)-1-piperidinyl-CH2xe2x80x94, 4-(N-hydroxyethylamino)-1-piperidinyl-CH2xe2x80x94, 4-(N-propylamino)-1-piperidinyl-CH2xe2x80x94, 1-methyl-4-piperazinyl-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, (2-methyl-1-imidazolyl-CH2xe2x80x94, 3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH2xe2x80x94, phthalimidylethylenyl, 1-azepanyl-CH2xe2x80x94, 1,4-dioxa-8-aza-spiro[4.5]decyl-CH2xe2x80x94, 4-(methyl)phenoxymethylenyl, 4-(N,N-dimethylaminomethylenyl)phenoxymethylenyl, methylaminothiocarbonyl, methoxymethylenyl, ethylaminothiocarbonyl, N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl, N-methylaminoethylenyl, N-methylaminomethylenyl, N-(hydroxypropyl)aminomethylenyl, N-ethylaminomethylenyl, Boc-aminoethoxymethylenyl, aminoethoxymethylenyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, 2-pyrrolidinylmethoxy, 1-methyl-2-pyrrolidinylmethoxy, azetidin-3-ylmethoxy, N-Boc-azetidin-3-ylmethoxy, N-Boc-piperidin-4-ylethoxy, 1-methyl-4-piperidinylethoxy, 4-piperidinylethoxy, 4-piperidinylmethoxy, N,N-dimethylaminoethoxy, 3-tetrahydrofuryl-Oxe2x80x94, 3-tetrahydrofurylmethoxy, 4-tetrahydrofurylmethoxy, 4-methylphenoxy, 4-(aminoethyl)phenoxy, 4-(1-imidazolyl)phenoxy, 2,4dimethylphenoxy, phenoxy, 4-cyanophenoxy, 4-[1,3]dioxolan-2-ylphenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy, ethoxycarbonyl, morpholinylethylenylaminocarbonyl, morpholinylpropylenylaminocarbonyl, 1-piperidinylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, N,N-diethylaminocarbonyl, N-(Nxe2x80x2,Nxe2x80x2-dimethylaminoethylenyl)aminocarbonyl, aminocarbonyl, morpholinylethylenylamino, morpholinylpropylenylamino, N,N-diethylamino, N,N-dimethylamino, N,N-diethylamino(2-propylenyl)aminomethylenyl, N,N-diethylamino(1-propylenyl)aminomethylenyl and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminoethylenyl)amino;
wherein Y is selected from 
preferably Y is selected from 
more preferably Y is selected from 
even more preferably Y is 
wherein R2 is selected from
a) lower alkylaminoalkynyl,
b) cycloalkenyl-C2-3-alkynyl,
c) cycloalkyl-C2-3-alkynyl,
d) phenyl-C2-3-alkynyl,
e) 5-6 membered heterocyclyl-C2-3-alkynyl,
f) substituted or unsubstituted cycloalkenyl,
g) substituted or unsubstituted phenyl,
h) substituted or unsubstituted 5-6 membered heterocyclyl, and
i) substituted or unsubstituted 5-6 membered heterocyclyl bridged with a phenyl group,
preferably substituted phenyl, substituted or unsubstituted 5-6 membered nitrogen-containing heteroaryl, and substituted or unsubstituted 5-6 membered nitrogen-containing heteroaryl fused with a phenyl group,
more preferably substituted or unsubstituted substituted phenyl or a substituted or unsubstituted heterocyclyl substituent selected from thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl and quinolyl,
even more preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, purinyl, isoquinolyl and quinolyl,
most preferably pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,
preferred pyridyl;
wherein substituted R2 is substituted with one or more substituents independently selected from halo, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94CO2R3, xe2x80x94CO2NR3R3, xe2x80x94COR3, xe2x80x94NR3R3, xe2x80x94C(O)NR3R3, xe2x80x94SO2NR R3, xe2x80x94NR3C(O)R3, xe2x80x94NHC(O)R3, xe2x80x94SO2NHC(O)R3, xe2x80x94C(S)NR3R3, nitro, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted heterocyclylalkylenyl, optionally substituted phenyl, optionally substituted phenoxyalkylenyl, optionally substituted heterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, lower alkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower (hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy, lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower ((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lower cyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl,
preferably selected from C1-C4 alkyl, C1-C2 haloalkyl, halo, amino, C1-C2-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, hydroxy, C1-C2-alkylthio, cyano, C1-C2-haloalkyloxy, aminosulfonyl, (6-membered N-containing heterocyclyl) sulfonyl, C1-C2-haloalkylaminocarbonyl, nitro, C1-C2-haloalkylcarbonylaminosulfonyl, C1-C2-alkylaminosulfonyl, C3-C6-cycloalkylaminosulfonyl, phenyl-C1-C2-alkylaminosulfonyl, (optionally substituted phenyl) aminosulfonyl, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, C1-C2-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, C1-C2-alkylcarbonylamino, morpholinyl-C1-C4-alkylenylamino, C1-C2-alkylamino and C1-C2-alkylamino-C1-C4-alkylenylamino, more preferably selected from nitro, methylcarbonylamino, aminosulfonyl, phenylsulfonylamino, morpholinylsulfonyl, trifluoroacetylaminosulfonyl, (4-chlorophenyl)aminosulfonyl, hydroxy, methylthio, cyano, trifluoromethoxy, bromo, chloro, fluoro, amino, methoxy, ethoxy, ethoxymethyl, trifluoromethylcarbonylamino, trifluoroethoxy, pyridyl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, carboxy, methylthio, piperidinyl, morpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl, methylaminothiocarbonyl, N-methylamino-methylenyl, N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl, N,N-dimethylamino, N-methylaminoethylenyl, N,N-diethylamino, morpholinylethylenylaminocarbonyl, morpholinylpropylenylaminocarbonyl, aminocarbonyl, morpholinylethylenylamino, morpholinylpropylenylamino, N,N-dimethylamino and N,N-di-methylaminoethylenylamino;
wherein R3 is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, C3-C6 cycloalkyl, and lower haloalkyl,
preferably H, C1-C3 alkyl, phenyl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, and C1-C3 haloalkyl;
more preferably H, methyl, ethyl, optionally substituted phenyl, benzyl, and trifluoromethyl;
wherein R6 is selected from H, alkyl, 5-6 membered heterocyclylalkylenyl and alkylamino,
preferably H;
wherein p is 1-2, preferably p is 1;
wherein q is 0 or 1; and
wherein r is 0, 1, 2 or 3, preferably 0 or 1, more preferably 0;
and pharmaceutically acceptable salts thereof;
provided A is not thiazol-2-yl when Y is ureido; further provided A is not phenyl when R2 is pyridyl or pyrimidyl when Y is ureido and when X and Z taken together form 1-methylindolyl; further provided A is not 1-phenylpyrazol-4-yl when Y is ureido when X and Z taken together form pyrazolyl and when R2 is pyrrol-1-yl; further provided A is not thiazolyl or dihydrothiazolyl when R2 is indolyl when Y is ureido and when X and Z taken together form thiazolyl or dihydrothiazolyl; provided A is not thiazolyl when R2 is 3-pyridyl when Y is ureido and when X and Z taken together form 2-(3-pyridyl)thiazol-4-yl; and further provided A is not thien-3-yl when Y is ureido when X and Z taken together form thienyl and when R2 is pyrrol-1-yl.
The invention also relates to compounds of Formula Ia 
The invention also relates to compounds of Formula I wherein A is selected from 
preferably A is 
and
wherein R is selected from H and C1-C3 alkyl; and
pharmaceutically acceptable salts thereof.
The invention also relates to compounds of Formula II 
wherein X1 is CR1 or N; wherein x is CR1 or N; wherein X3 is CH or N; provided only one of X1, X2 and X3 can be N;
wherein R1 is one or more substituents selected from H, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C1-C6-alkyl, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, halo, hydroxy, (optionally substituted pyrrolidinyl)-C1-C2-alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, morpholinyl-C1-C2-alkyl, (optionally substituted imidazolyl)-C1-C2-alkyl, phthalimidyl-C1-C2-alkyl, optionally substituted azepanyl-C1-C2-alkyl, 1,4-dioxa-8-aza-spiro[4.5]decyl-C1-C2-alkyl, optionally substituted phenoxy-C1-C2-alkyl, C1-C4-alkylaminothiocarbonyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, amino-C1-C4-alkoxy-C1-C4-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryl-Oxe2x80x94, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted pyridyloxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino;
wherein R2 is selected from halo, C1-C4-alkyl, C1-C4-alkylamino-C2-C4-alkynyl, C3-C6-cycloalkyl, optionally substituted benzodioxolyl, optionally substituted indolyl, optionally substituted phenoxy, unsubstituted 5-membered oxygen or sulfur containing heteroaryl, unsubstituted 6-membered nitrogen-containing heterocyclyl, phenyl optionally substituted with one or two substituents selected
from halo, C1-C4-alkylamino, amino, nitro, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, (optionally substituted phenyl)sulfonylamino, cyano, C1-C2-haloalkoxy, 5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl and (optionally substituted phenyl)aminosulfonyl, and
6-membered nitrogen-containing heterocyclyl substituted with one or more substituents independently selected from pyridyl, phenyl,
C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, amino, halo, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, N,N-di-C1-C2-alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C2 alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, C1-C2-haloalkylcarbonylamino, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2-alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino; and
wherein Y2 is selected from O, NH and CH2;
and pharmaceutically acceptable salts thereof.
The invention also relates to compounds of Formula III 
wherein X1 is CR1 or N; wherein X2 is CR1 or N; wherein X3 is CH or N; provided only one of X1, X2 and X3 can be N; preferably X1 is CR1; X2 is CR1; X3 is CH; provided X2 is CH when X1 is not CH;
wherein R1 is one or more substituents independently selected from H, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C1-C6-alkyl, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, halo, hydroxy, (optionally substituted pyrrolidinyl)-C1-C2-alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, morpholinyl-C1-C2-alkyl, (optionally substituted imidazolyl)-C1-C2-alkyl, phthalimidyl-C1-C2-alkyl, optionally substituted azepanyl-C1-C2-alkyl, 1,4-dioxa-8-aza-spiro[4.5]decyl-C1-C2-alkyl, optionally substituted phenoxy-C1-C2-alkyl, C1-C4-alkylaminothiocarbonyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, amino-C1-C4-alkoxy-C1-C4-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryl-Oxe2x80x94, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted pyridyloxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino, preferably H, methyl, ethyl, propyl, 1-methyl-4-piperazinyl, l-benzyl-4-piperazinyl, 1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl, 1-ethyl-4-piperazinyl, 1-piperidinyl-CH2xe2x80x94, 4-methyl-1-piperidinyl-CH2xe2x80x94, 3-methyl-1-piperidinyl-CH2xe2x80x94, 2-methyl-1-piperidinyl-CH2xe2x80x94, 3,5-dimethyl-1-piperidinyl-CH2xe2x80x94, 4-oxo-1-piperidinyl-CH2xe2x80x94, 4-hydroxy-1-piperidinyl-CH2xe2x80x94, 3-hydroxy-1-piperidinyl-CH2xe2x80x94, 2-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-carboxy-1-piperidinyl-CH2xe2x80x94, 4-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 4-carboxy-1-piperidinyl-CH2xe2x80x94, 4-(1-pyrrolidinyl)-1-piperidinyl-CH2xe2x80x94, 4-(N-hydroxyethylamino)-1-piperidinyl-CH2xe2x80x94, 4-(N-propylamino)-1-piperidinyl-CH2xe2x80x94, 3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl, N-methylaminomethylenyl, N-ethylaminomethylenyl and N,N-diethylamino,
more preferably ethyl, propyl, 1-methyl-4-piperazinyl, 1-piperidinyl-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, N,N-diethylaminomethylenyl and N,N-diethylamino; and
wherein R2 is selected from halo, C1-C4-alkyl, C1-C4-alkylamino-C2-C4-alkynyl, C3-C6-cycloalkyl, optionally substituted benzodioxolyl, optionally substituted indolyl, optionally substituted phenoxy, unsubstituted 5-membered oxygen or sulfur containing heteroaryl, unsubstituted 5- or 6-membered nitrogen-containing heterocyclyl, phenyl optionally substituted with one or two substituents selected
from halo, C1-C4-alkylamino, amino, nitro, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, (optionally substituted phenyl)sulfonylamino, cyano, C1-C2-haloalkoxy, 5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl and (optionally substituted phenyl)aminosulfonyl, and
6-membered nitrogen-containing heterocyclyl substituted with one or more substituents independently selected from pyridyl, phenyl,
C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, amino, halo, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, N,N-di-C1-C2-alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C2-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, C1-C2-haloalkylcarbonylamino, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2 alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino,
preferably 3-(N,N-dimethylamino)-1-propynyl, 3-fluorophenyl, 4-fluorophenyl, 4-(N,N-dimethylamino)phenyl, 3-(methylcarbonylamino)phenyl, phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminophenyl, 3-aminophenyl, 4-aminosulfonylphenyl, 4-(4-morpholinylsulfonyl)phenyl, 4-(trifluoroacetylaminosulfonyl)phenyl, 4-(trifluoromethylcarbonylaminosulfonyl)phenyl, 4-[(4-chlorophenyl)aminosulfonyl]phenyl, 3-(phenylsulfonylamino)phenyl, 2,4-difluorophenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-methylthiophenyl, 4-cyanophenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 3-nitrophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-thiazolyl, 2-pyrazinyl, 5-pyrimidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl, 6-methoxy-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 3,4-dichloro-4-pyridyl, 6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl, 3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl, 3-pyridyl and 4-pyridyl,
more preferably 5-pyrimidinyl, 2-pyrazinyl, morpholinyl, 4-methylpiperazinyl, 4-fluorophenyl, 4-(N,N-dimethylamino)propynyl, 3-nitrophenyl, 3-aminophenyl, 4-aminosulfonylphenyl, 3-aminosulfonylphenyl, 3-(phenylsulfonylamino)phenyl, 3-(methylcarbonylamino)phenyl, 4-[(trifluoromethylcarbonyl)aminosulfonyl]phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-thiazolyl, 6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl, 3-pyridyl and 4-pyridyl;
and pharmaceutically acceptable salts thereof.
The invention also relates to compounds of Formula IV 
wherein X1 is CR1 or N; wherein X2 is CR1 or N; wherein X3 is CH or N; provided only one of X1, X2 and X3 can be N; preferably X1 is CR1; X is CR1; X is CH; provided X2 is CH when X1 is not CH;
wherein R1 is one or more substituents selected from H, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C1-C6-alkyl, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, halo, hydroxy, (optionally substituted pyrrolidinyl)-C1-C2-alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, morpholinyl-C1-C2-alkyl, (optionally substituted imidazolyl)-C1-C2-alkyl, phthalimidyl-C1-C2-alkyl, optionally substituted azepanyl-C1-C2-alkyl, 1,4-dioxa-8-aza-spiro[4.5]decyl-C1-C2-alkyl, optionally substituted -phenoxy-C1-C2-alkyl, C1-C4-alkylaminothiocarbonyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, amino-C1-C4-alkoxy-C1-C4-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryl-Oxe2x80x94, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted pyridyloxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino,
preferably methyl, ethyl, propyl, 1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl, 1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl, 1-ethyl-4-piperazinyl, 1-piperidinyl-CH2xe2x80x94, 4-methyl-1-piperidinyl-CH2xe2x80x94, 3-methyl-1-piperidinyl-CH2xe2x80x94, 2-methyl-1-piperidinyl-CH2xe2x80x94, 3,5-dimethyl-1-piperidinyl-CH2xe2x80x94, 4-oxo-1-piperidinyl-CH2xe2x80x94, 4-hydroxy-1-piperidinyl-CH2xe2x80x94, 3-hydroxy-1-piperidinyl-CH2xe2x80x94, 2-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-carboxy-1-piperidinyl-CH2xe2x80x94, 4-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 4-carboxy-1-piperidinyl-CH2xe2x80x94, 4-(1-pyrrolidinyl)-1-piperidinyl-CH2xe2x80x94, 4-(N-hydroxyethylamino)-1-piperidinyl-CH2xe2x80x94, 4-(N-propylamino)-1-piperidinyl-CH2xe2x80x94, 3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl, N-methylaminomethylenyl, N-ethylaminomethylenyl and N,N-diethylamino, and
more preferably ethyl, propyl and 1-methyl-4-piperazinyl; and
wherein R2 is halo, C1-C4-alkyl, C1-C4-alkylamino-C2-C4-alkynyl, C3-C6-cycloalkyl, optionally substituted benzodioxolyl, optionally substituted indolyl, optionally substituted phenoxy, 5-membered oxygen or sulfur containing heteroaryl, 5- or 6-membered nitrogen-containing heterocyclyl, phenyl optionally substituted with one or two substituents selected
from halo, C1-C4-alkylamino, amino, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, cyano, C1-C2-haloalkyloxy, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl, and (optionally substituted phenyl)aminosulfonyl, and
6-membered nitrogen-containing heterocyclyl substituted with one or more substituents
independently selected from pyridyl, phenyl, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, halo, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, N,N-di-C1-C2-alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C2-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2-alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino,
preferably 3-fluorophenyl, 4-fluorophenyl, 4-(N,N-dimethylamino)phenyl, 3-(methylcarbonylamino)phenyl, phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminophenyl, 3-aminophenyl, 4-aminosulfonylphenyl, 4-(4-morpholinylsulfonyl)phenyl, 4-(trifluoroacetylaminosulfonyl)phenyl, 4-(trifluoromethylcarbonylaminosulfonyl)phenyl, 4-[(4-chlorophenyl)aminosulfonyl]phenyl, 3-(phenylsulfonylamino)phenyl, 2,4-difluorophenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-methylthiophenyl, 4-cyanophenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 3-nitrophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-thiazolyl, 2-pyrazinyl, 5-pyrimidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl, 6-methoxy-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 3,4-dichloro-4-pyridyl, 6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl, 3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl, 3-pyridyl and 4-pyridyl, and more preferably 4-pyridyl;
and pharmaceutically acceptable salts thereof.
The invention also relates to compounds of Formula V 
wherein R7 is selected from halo, C1-C4-alkyl, C3-C6-cycloalkyl, optionally substituted benzodioxolyl, optionally substituted indolyl, optionally substituted phenoxy, 5-membered oxygen or sulfur containing heteroaryl, 6-membered nitrogen-containing heterocyclyl, phenyl optionally substituted with one or two substituents selected
from halo, C1-C4-alkylamino, amino, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, cyano, C1-C2-haloalkyloxy, aminosulfonyl, (6-membered N-containing heterocyclyl) sulfonyl, C1-C2haloalkylcarbonylaminosulfonyl, and (optionally substituted phenyl)aminosulfonyl, and
6-membered nitrogen-containing heterocyclyl substituted with one or more substituents
independently selected from pyridyl, phenyl, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, halo, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, N,N-di-C1-C2 alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C2-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2-alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino,
preferably halo, C1-C4-alkyl, C3-C6-cycloalkyl, optionally substituted pyrimidinyl, morpholinyl, optionally substituted piperidinyl, optionally substituted benzodioxolyl, optionally substituted indolyl, optionally substituted phenoxy, optionally substituted thienyl, phenyl optionally substituted with one or two substituents
selected from halo, C1-C4-alkylamino, Boc-amino, amino, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, cyano, C1-C2-haloalkyloxy, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl, and (optionally substituted phenyl)aminosulfonyl,
and pyridyl optionally substituted with one or two substituents selected from C1-C3 alkyl, C1-C4-alkoxy and halo,
more preferably bromo, chloro, fluoro, C1-C3-alkyl, C3-C6-cycloalkyl, optionally substituted pyrimidinyl, morpholinyl, piperidinyl, -benzodioxolyl, indolyl, phenoxy, thienyl, phenyl optionally
substituted with one or two substituents selected from fluoro, N,N-dimethylamino, amino, methoxy, trifluoromethyl, Boc-amino, hydroxy, ethoxy, methylthio, cyano, trifluoromethoxy, aminosulfonyl, 4-morpholinylsulfonyl, trifluoroacetylaminosulfonyl, and (4-chlorophenyl)aminosulfonyl,
and pyridyl optionally substituted with one or two substituents selected from C1-C3 alkyl, methoxy, ethoxy and chloro,
even more preferably bromo, methyl, ethyl, cyclopropyl, cyclohexyl, 3-fluorophenyl, 4-fluorophenyl, 4-(N,N-dimethylamino phenyl, phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminophenyl, 3-aminophenyl, 4-Boc-aminophenyl, 4-aminosulfonylphenyl, 4-(4-morpholinylsulfonyl)phenyl, 4-(trifluoroacetylaminosulfonyl)phenyl, 4-[(4-chlorophenyl)aminosulfonyl]phenyl, 2,4-difluorophenyl, 5-benzodioxolyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl, 4-methylthiophenyl, 5-indolyl, 4-cyanophenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, phenoxy, 2-thienyl, 4-pyrimidinyl, 2-methylthio-4-pyrimidinyl, morpholinyl, 4-piperidinyl, 6-methoxy-3-pyridyl, 2-methoxy-3-pyridyl, 2-ethoxy-3-pyridyl, 3,4-dichloro-4-pyridyl, 3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl, 3-pyridyl and 4-pyridyl; and
wherein R8 is selected from 
wherein R8 is optionally substituted with one or two substituents independently selected from H, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C1-C6-alkyl, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, halo, hydroxy, ((optionally substituted pyrrolidinyl)-C1-C2-alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, morpholinyl-C1-C2-alkyl, (optionally substituted imidazolyl)-C1-C2-alkyl, phthalimidyl-C1-C2-alkyl, optionally substituted azepanyl-C1-C2-alkyl, 1,4-dioxa-8-aza-spiro[4.5]decyl-C1-C2-alkyl, optionally substituted phenoxy-C1-C2-alkyl, C1-C4-alkylaminothiocarbonyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, amino-C1-C4-alkoxy-C1-C4-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted -piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryl-Oxe2x80x94, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted pyridyloxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino,
preferably unsubstituted or substituted with one or more substituents selected from pyridyl, phenyl, C1-C4 alkyl, C1-C2 haloalkyl, halo, piperidinyl, morpholinyl, methylpiperazinyl, methylaminothiocarbonyl, N,N-diethylaminomethylenyl, N-methylaminomethylenyl, morpholinylpropylenylaminocarbonyl, aminocarbonyl morpholinylpropylenylamino, N,N-diethylamino and N,N-dimethylaminoethylenylamino;
wherein R9 is selected from optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, amino, C1-C2 azidoalkyl, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, halo, (optionally substituted pyrrolidinyl)CH2xe2x80x94, (optionally substituted piperidinyl)-CH2xe2x80x94, (optionally substituted piperazinyl)-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, (optionally substituted imidazolyl)-CH2xe2x80x94, phthalimidylethyl, optionally substituted azepanyl-CH2xe2x80x94, 1,4-dioxa-8-aza-spiro[4.5]decyl-CH2xe2x80x94, optionally substituted phenoxy-CH2xe2x80x94, C1-C4-alkylaminothiocarbonyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino-C1-C4-alkyl, Boc-aminoethoxymethylenyl, amino-C1-C4-alkoxy-C1-C4-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryl-Oxe2x80x94, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, heterocyclyl-C1-C4-alkylaminocarbonyl, 1-piperidinylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, morpholinyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino,
preferably 3-(N,N-dimethylamino)-1-pyrrolidinyl, 1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl, 1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl, 1-ethyl-4-piperazinyl, 4-amino-1-piperidinyl, 4-(N-hydroxyethylamino)-1-piperidinyl, 4-(N-propylamino)-1-piperidinyl, 4-(N-benzylamino)-1-piperidinyl, 4-oxo-piperidinyl, 4-(hydroxyimino)-piperidinyl, 4-morpholinyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, methyl, ethyl, propyl, amino, azidomethyl, hydroxymethyl, trifluoromethyl, fluoro, chloro, bromo, aminoethyl, aminomethyl, cyanomethyl, 1-pyrrolidinyl-CH2xe2x80x94, 2-methoxycarbonyl-1-pyrrolidinyl-CH2xe2x80x94, 2-carboxy-1-pyrrolidinyl-CH2xe2x80x94, 2-hydroxymethyl-1-pyrrolidinyl-CH2xe2x80x94, 1-piperidinyl-CH2xe2x80x94, 4-methyl-1-piperidinyl-CH2xe2x80x94, 3-methyl-1-piperidinyl-CH2xe2x80x94, 2-methyl-1-piperidinyl-CH2xe2x80x94, 3,5-dimethyl-1-piperidinyl-CH2xe2x80x94, 4-oxo-1-piperidinyl-CH2xe2x80x94, 4-hydroxy-1-piperidinyl-CH2xe2x80x94, 3-hydroxy-1-piperidinyl-CH2xe2x80x94, 2-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 3-carboxy-1-piperidinyl-CH2xe2x80x94, 4-ethoxycarbonyl-1-piperidinyl-CH2xe2x80x94, 4-carboxy-1-piperidinyl-CH2xe2x80x94, 4-(1-pyrrolidinyl)-1-piperidinyl-CH2xe2x80x94, 4-(N-hydroxyethylamino)-1-piperidinyl-CH2xe2x80x94, 4-(N-propylamino)-1-piperidinyl-CH2xe2x80x94, 1-methyl-4-piperazinyl-CH2xe2x80x94, 4-morpholinyl-CH2xe2x80x94, (2-methyl-1-imidazolyl-CH2xe2x80x94, 3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH2xe2x80x94, phthalimidylethyleneyl, 1-azepanyl-CH2xe2x80x94, 1,4-dioxa-8-aza-spiro[4.5]decyl-CH2xe2x80x94, 4-(methyl)phenoxymethylenyl, 4-(N,N-dimethylaminomethylenyl)phenoxymethylenyl, methylaminothiocarbonyl, methoxymethylenyl, ethylaminothiocarbonyl, N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl, N-methylaminomethylenyl, N-(hydroxypropyl)aminomethylenyl, N-ethylaminomethylenyl, Boc-aminoethoxymethylenyl, aminoethoxymethylenyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, 2-pyrrolidinylmethoxy, 1-methyl-2-pyrrolidinylmethoxy, azetidin-3-ylmethoxy, N-Boc-azetidin-3-ylmethoxy, N-Boc-piperidin-4-ylethoxy, 1-methyl-4-piperidinylethoxy, 4-piperidinylethoxy, 4-piperidinylmethoxy, N,N-dimethylaminoethoxy, 3-tetrahydrofuryl-Oxe2x80x94, 3-tetrahydrofurylmethoxy, 4-tetrahydrofurylmethoxy, 4-methylphenoxy, 4-(aminoethyl)phenoxy, 4-(1-imidazolyl)phenoxy, 2,4-dimethylphenoxy, phenoxy, 4-cyanophenoxy, 4-[1,3]dioxolan-2-ylphenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy, ethoxycarbonyl, morpholinylpropylenylaminocarbonyl, 1-piperidinylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, N,N-diethylaminocarbonyl, N-(Nxe2x80x2,Nxe2x80x2-dimethylaminoethylenyl)aminocarbonyl, aminocarbonyl, morpholinylpropylenylamino, N,N-diethylamino, N,N-diethylamino(2-propylenyl)aminomethylenyl, N,N-diethylamino(1-propylenyl)aminomethylenyl and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminoethylenyl)amino;
wherein R10 is selected from H, hydroxy, and amino;
wherein R11 is selected from pyridyl and pyrimidinyl, preferably pyridyl; and
wherein R12 is selected from H, and C1-C4 alkyl, preferably H, methyl, ethyl and propyl;
and pharmaceutically acceptable salts thereof.
The invention also relates to compounds of Formula VI 
wherein R15 is one or more substituents selected from H, optionally substituted heterocyclyl, phenyl, C1-C6-alkyl, C1-C2-haloalkyl, C1-C4-hydroxyalkyl, amino, C1-C4-azidoalkyl, C1-C4-cyanoalkyl, C1-C4-aminoalkyl, halo, hydroxy, (optionally substituted heterocyclyl)-C1-C4-alkyl, optionally substituted phenoxy-C1-C2-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino, amino-C1-C4-alkoxy-C1-C4-alkyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, optionally substituted phenoxy, C1-C4-alkoxycarbonyl, 5-6-membered heterocyclyl-C1-C4-alkylaminocarbonyl, 5-6-membered N-containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylaminothiocarbonyl, C1-C4-alkylamino-C1-C4-alkylaminocarbonyl, aminocarbonyl, 5-6-membered N-containing heterocyclyl-sulfonyl-C1-C4-alkyl, 5-6-membered N-containing heterocyclyl-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino-C1-C4-alkylamino-C1-C4-alkyl, and C1-C4-alkylamino-C1-C4-alkylamino;
preferably H, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, morpholinyl, 1,2,3,6-tetrahydro-pyridinyl, (optionally substituted pyrrolidinyl)-C1-C2-alkyl, (optionally substituted piperidinyl)-C1-C2-alkyl, (optionally substituted piperazinyl)-C1-C2-alkyl, morpholinyl-C1-C2-alkyl, C1-C4-alkylamino-C1-C4-alkyl, C1-C4-hydroxyalkylamino, (optionally substituted pyrrolidinyl)-C1-C2-alkylamino, (optionally substituted piperidinyl)-C1-C2-alkylamino, (optionally substituted piperazinyl)-C1-C2-alkylamino, morpholinyl-C1-C2-alkylamino, optionally substituted pyrrolidinyl-C1-C4-alkoxy, optionally substituted azetidinyl-C1-C4-alkoxy, tetrahydrofuryl-C1-C4-alkoxy, optionally substituted piperidinyl-C1-C4-alkoxy, C1-C4-alkylamino-C1-C4-alkoxy, tetrahydrofuryloxy, optionally substituted piperidinyloxy, optionally substituted phenoxy, C1-C4-alkylaminocarbonyl and C1-C4-alkylaminothiocarbonyl;
more preferably H, tetrahydro-furanyloxy, 1-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidinylmethoxy, 3-pyrrolidinylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy, 4-piperidinylmethoxy, 1-Boc-piperidin-4-ylmethoxy, 1-Boc-piperidin-4-ylethoxy, piperidin-4-ylethoxy, 1-methyl-piperidin-4-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, 1-methyl-azetidin-3-ylmethoxy, 3-azetidinylmethoxy, 1-methyl-piperidin-4-yloxy, phenyloxy, 4-(pyrrolidin-1-ylmethyl)phenoxy, dimethylaminoethoxy, piperidinylethylamino, 1-piperidinylmethyl, 1-(piperidin-1-yl) ethyl, 3-methylpiperidin-1-ylmethyl, 1-pyrrolidinylmethyl, 2,2,6,6-tetramethylpiperidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminothiocarbonyl, diethylaminocarbonyl, N-Boc-N-isopropylaminomethyl, isopropylaminomethyl, 2-thienylsulfonylmethyl, hydroxypropylamino, 4-ethyl-piperidin-1-yl, 4-(2-pyridyl)piperidin-1-yl, 1-methylpiperidin-4-yl, 4-(2-pyrazinyl)piperidin-1-yl, 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl, 1,2,3,6-tetrahydro-pyridin-4-yl, and 1-Boc-1,2,3,6-tetrahydro-pyridin-4-yl;
wherein R16 is selected from H, heterocyclylcarbonyl, alkylaminocarbonyl, alkylaminomethyl, and heterocyclylmethyl;
preferably H, 5-6-membered nitrogen containing heterocyclylcarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-alkylaminomethyl, and 5-6-membered nitrogen containing heterocyclylmethyl;
more preferably H, 1-piperidinylcarbonyl, diethylaminocarbonyl, diethylaminomethyl, 1-piperidinylmethyl; and
wherein R17 is selected from
halo, and preferably chloro and bromo,
C1-C3-alkyl, preferably C1-C2-alkyl, and more preferably methyl,
cycloalkylalkynyl, preferably C3-C6-cycloalkyl-C2-C4-alkynyl, and more preferably cyclopropylethynyl,
cycloalkyl, preferably C3-C6-cycloalkyl, and more preferably cyclopropyl,
optionally substituted heteroarylsulfonyl-C1-C4-alkyl, and preferably optionally substituted 5-6-membered heteroarylsulfonyl-C1-C2-alkyl,
optionally substituted indolyl, and preferably 1-Boc-indol-5-yl,
optionally substituted phenoxy,
optionally substituted indazolyl, and preferably 5-indazolyl,
unsubstituted 5-membered oxygen or sulfur containing heteroaryl, and preferably unsubstituted thienyl, and 5-tert-butyloxazol-2-yl,
unsubstituted 6-membered nitrogen-containing heterocyclyl,
phenyl optionally substituted with one or two substituents selected from halo, C1-C4-alkylamino, amino, nitro, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, (optionally substituted phenyl)sulfonylamino, cyano, C1-C2-haloalkoxy, 5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl and (optionally substituted phenyl)aminosulfonyl, and
preferably optionally substituted with one or two substituents selected from halo, C1-C4-alkylamino, amino, nitro, C1-C4-alkoxy, C1-C2-haloalkyl, hydroxy, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, (optionally substituted phenyl)sulfonylamino, cyano, C1-C2-haloalkoxy, 5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl, C1-C2-haloalkylcarbonylaminosulfonyl and (optionally substituted phenyl)aminosulfonyl; and more preferably and phenyl optionally substituted with aminosulfonyl, and
6-membered nitrogen-containing heterocyclyl substituted with one or more substituents independently selected from pyridyl, phenyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, amino, halo, piperidinyl, morpholinyl, C1-C4 alkylpiperazinyl, C1-C4 alkylaminothiocarbonyl, N,N-di-C1-C4-alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C4-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, C1-C4-haloalkylcarbonylamino, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2-alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino;
preferably pyridyl, phenyl, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, amino, halo, piperidinyl, morpholinyl, C1-C2 alkylpiperazinyl, C1-C3 alkylaminothiocarbonyl, N,N-di-C1-C2-alkylamino-C1-C4-alkylenyl, Nxe2x80x94C1-C2-alkylamino-C1-C4-alkylenyl, morpholinyl-C1-C4-alkylenylaminocarbonyl, aminocarbonyl, C1-C2-haloalkylcarbonylamino, morpholinyl-C1-C4-alkylenylamino, N,N-di-C1-C2-alkylamino and N,N-di-C1-C2-alkylamino-C1-C4-alkylenylamino, and
more preferably 4-pyridyl substituted with one or more substituents independently selected from methoxy and chloro;
and pharmaceutically acceptable derivatives thereof; provided only one of R15 and R16 is H.
A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-[4-(Piperidine-1-carbonyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-(2-Chloro-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;
N,N-Diethyl-2-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-isonicotinamide;
N,N-Diethyl-2-[3-(2-phenyl-thiazol-4-yl)-ureido]-isonicotinamide;
2-[3-(2-Bromo-thiazol-4-yl)-ureido]-N,N-diethyl-isonicotinamide;
1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(1-Piperidin-1-yl-ethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
1-{6-[(Piperidin-2-ylmethyl)-amino]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
(S)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
(R)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-(2-Chloro-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;
1-(2-Bromo-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;
1-(2-Chloro-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;
1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-bromo-thiazol-4-yl)-urea;
1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-chloro-thiazol-4-yl)-urea;
1-(2-Bromo-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;
1-(2-Chloro-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;
3-(4-{3-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureido}-thiazol-2-yl)-benzenesulfonamide;
tert-Butyl 3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate;
1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-urea;
1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;
1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
Isopropyl-{6-[3-(2-phenyl-thiazol-4-yl)-ureido-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester;
1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-(2-Bromo-thiazol-4-yl)-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea;
1-(2-Bromo-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;
1-(2-Chloro-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;
1-(2-phenylthiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;
1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-urea;
1-[2-(1H-Indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;
1-(1xe2x80x2-Methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-(2-Bromo-thizol-4-yl)-3-(1xe2x80x2-methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl-6-yl)-urea;
1-(1-Methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-2[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;
1-[6-(3-Hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-urea;
1-(2-Bromo-thiazol-4-yl)-3-[6(3-hydroxy-propylamino)-pyridin-2-yl]-urea;
1-(1xe2x80x2-Methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-hexahydro-[2,4xe2x80x2]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-(1-Methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-hexahydro-[2,4xe2x80x2]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;
6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3xe2x80x2,6xe2x80x2-dihydro-2xe2x80x2H-[2,4]bipyridinyl-1xe2x80x2-carboxylic acid tert-butylester;
1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl-6-yl)-urea;
1-(2-Pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-urea;
2-[6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester;
1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;
6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioic acid diethylamide;
1-(2-Bromo-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;
1-(2-Chloro-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;
1-(2-Phenyl-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;
1-(2-Bromo-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;
1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-phenoxy-pyridin-2-yl)-urea;
1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;
1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yl]-3-[2-(2-methoxy-pyridin-4-yl)-thiazol-4-yl]-urea;
1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-(2-phenylthiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)urea;
1-(6-Diethylaminomethylpyridin-2-yl)-3-(2-phenylthiazol-4-yl)urea;
(S)-1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;
1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-phenylthiazol-4-yl]urea;
1-[6-(4-Ethylpiperazin-1-yl)-pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;
1-(2-phenylthiazol-4-yl)-3-[6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridin-2-yl]urea;
Diethyl 6-[3-(2-phenylthiazol-4-yl)ureido]-pyridine-2-carboxamide;
1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;
1-(2-Bromothiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;
1-[6-(Piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;
1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-(2-Phenyl-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;
1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;
1-[6-(2-Piperidin-4-yl-ethoxy)-pyridin-2-yl]-3-(2-thiophen-2-yl-thiazol-4-yl)-urea;
1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-[2-(thiophene-2-sulfonylmethyl)-thiazol-4-yl]-urea;
1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea; and
[2-(2-Chloro-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea.
Indications
Compounds of the present invention would be useful for, but not limited to, the treatment of cell proliferative diseases or of apoptosis.
The compounds of the invention are endowed with kinase inhibitory activity, such as CDK/cyclin kinase inhibitory activity and GSK inhibitory activity.
The compounds of the invention are useful in therapy as antineoplasia agents.
Compounds of the invention would be useful for the treatment of neoplasia including cancer, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-Lymphoma, Hodgkin""s lymphoma, non-Hodgkin""s lymphoma, hairy cell lymphoma and Burkett""s lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi""s sarcoma).
Preferably, the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer.
Due to the key role of CDKs in the regulation of cellular proliferation, these compounds are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, blood vessel proliferative disorders including arthritis and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies; metabolic disorders including psoriasis, diabetes mellitus, chronic wound healing, inflammation, and diabetic retinopathy and other vision disorders; and others including benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, pulmonary fibrosis, angiogenesis, metastasis, vascular smooth cell proliferation, post-surgical stenosis and hypertrophic scar formation, eczema, inflammatory bowel disease, endotoxic shock, and fungal infections.
The compounds of the invention are useful to prevent the phosphorylation of tau protein.
The compounds of the invention are useful in the treatment of neurological disorders, including neurological injuries and neurodegenerative diseases, such as, but not limited to, stroke, brain trauma, epilepsy, spinal cord injury, ischemia, multiple sclerosis, vision related disorders including but not limited to glaucoma and macular degeneration, hearing loss, AIDS-related dementia, retinitis pigmentosa, spinal muscular atrophy, cerebellar degeneration, amyotrophic lateral sclerosis, Parkinson""s disease, Huntington""s disease and Alzheimer""s disease.
Compounds of Formula I-VI, as inhibitors of the CDKs, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections, including but not limited to HIV, human papilloma virus, herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus.
The compounds of this invention may also act as inhibitors of other protein kinases, e.g. KDR, IKK, JNK3, and thus be effective in the treatment of diseases associated with other protein kinases.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
Inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not misregulated, but is nonetheless essential for maintenance of the disease state. In this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases. For example, many viruses, such as human papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle. Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2, may disrupt the virus life cycle by preventing virus replication. This same principle may be used to protect normal cells of the body from toxicity of cycle-specific chemotherapeutic agents. Inhibition of CDK2 or CDK4 will prevent progression into the cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis. Furthermore, CDK2/cyclin E activity has also been shown to regulate NF-xcexaB: Inhibition of CDK2 activity stimulates NF-xcexaB-dependent gene expression, an event mediated through interactions with the p300 coactivator. NF-xcexaB regulates genes involved in inflammatory responses, (such as hematopoietic growth factors chemokines and leukocyte adhesion molecules) and may be involved in the suppression of apoptotic signals within the cell. Thus, inhibition of CDK2 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-xcexaB. Inhibition of CDK2 activity may also have utility in other cases where regulation of NF-KB plays a role in etiology of disease. A further example may be taken from fungal infections: Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A may cause arrest or death in the fungi, improving the therapeutic outcome for patients with these infections.
The compounds of the invention are useful as modulators of apoptosis. As such they are useful in the prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis and autoimmune diabetes mellitus), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, vision related disorders including but not limited to glaucoma and macular degeneration, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis) aspirin-sensitive rhinosinusitis, cystic fibrosis, kidney diseases and cancer pain.
Definitions
The term xe2x80x9cpreventionxe2x80x9d includes either preventing the onset of disorders altogether or delaying the onset of a preclinically evident stage of disorders in individuals. This includes prophylactic treatment of those at risk of developing a disease, such as a cancer, for example.
The phrase xe2x80x9ctherapeutically-effectivexe2x80x9d is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. For example, effective neuroplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm. Alternatively, effective therapeutic agents for the treatment of neurological disorders minimize the damage from injury, improve cognitive functions, and the like.
The term xe2x80x9cHxe2x80x9d denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylaminoxe2x80x9d, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. Even more preferred are lower alkyl radicals having one to four carbon atoms. The term xe2x80x9calkylenylxe2x80x9d embraces bridging divalent alkyl radicals such as methylenyl and ethyleneyl.
The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having at least one carbonxe2x80x94carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are xe2x80x9clower alkenylxe2x80x9d radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d, embrace radicals having xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d orientations, or alternatively, xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d orientations.
The term xe2x80x9calkynylxe2x80x9d denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are xe2x80x9clower alkynylxe2x80x9d radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of tie same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. xe2x80x9cPerfluoroalkylxe2x80x9d means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
The term xe2x80x9cazidoalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more azido (N3) radicals. More preferred azidoalkyl radicals are xe2x80x9clower azidoalkylxe2x80x9d radicals having one to six carbon atoms and one azido radical. Examples of such radicals include azidomethyl. Even more preferred are lower azidoalkyl radicals having one to three carbon atoms.
The term xe2x80x9ccyanoalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more cyano (CN) radicals. More preferred cyanoalkyl radicals are xe2x80x9clower cyanoalkylxe2x80x9d radicals having one to six carbon atoms and one cyano radical. Examples of such radicals include cyanomethyl. Even more preferred are lower cyanoalkyl radicals having one to three carbon atoms.
The term xe2x80x9cphenyloxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more phenoxy radicals. More preferred phenyloxyalkyl radicals are xe2x80x9clower phenyloxyalkylxe2x80x9d radicals having one to six carbon atoms and one phenoxy radical. Examples of such radicals include phenoxymethyl.
The term xe2x80x9calkoxyxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term xe2x80x9calkoxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more alkoxy radicals. More preferred alkoxyalkyl radicals are xe2x80x9clower alkoxyalkylxe2x80x9d radicals having one to six carbon atoms and one alkoxy radical. Examples of such radicals include methoxymethyl.
The term xe2x80x9caminoalkoxyalkylxe2x80x9d embraces alkoxyalkyl radicals, as defined above, where any one carbon atom may be substituted with one amino radical. More preferred aminoalkoxyalkyl radicals are xe2x80x9clower aminoalkoxyalkylxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include aminoethoxymethyl.
The term xe2x80x9calkylaminoalkoxyxe2x80x9d embraces alkoxy radicals, as defined above, substituted with an alkylamino radical. More preferred alkylaminoalkoxy radicals are xe2x80x9clower alkylaminoalkoxyxe2x80x9d radicals having alkoxy groups with one to six carbon atoms and an alkylamino radical with one to six carbon atoms. Examples of such radicals include methylaminomethoxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl. Said xe2x80x9carylxe2x80x9d group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing xe2x80x94Oxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94Sxe2x80x94 or xe2x80x94Sxe2x80x94Sxe2x80x94 portions. Said xe2x80x9cheterocyclylxe2x80x9d group may have 1 to 3 substituents such as BOC, hydroxyl, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Examples of unsaturated heterocyclic radicals, also termed xe2x80x9cheteroarylxe2x80x9d radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
The term also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, -indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl].
The term also includes bridged, spiro and oxo-containing heterocyclic rings, such as 1,4-dioxa-8-aza-spiro[4.5]decyl, phthalimidyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, and (1-aza-bicyclo[2.2.2]oct-3-yl).
Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Even more preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94.
The terms xe2x80x9csulfamyl,xe2x80x9d xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidyl,xe2x80x9d whether alone or used with terms such as xe2x80x9cN-alkylaminosulfonylxe2x80x9d, xe2x80x9cN-arylaminosulfonylxe2x80x9d, xe2x80x9cN,N-dialkylaminosulfonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminosulfonylxe2x80x9d, denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (xe2x80x94SO2NH2).
The term xe2x80x9calkylaminosulfonylxe2x80x9d includes xe2x80x9cN-alkylaminosulfonylxe2x80x9d and xe2x80x9cN,N-dialkylaminosulfonylxe2x80x9d where sulfamyl radicals are substituted, respectively, with one alkyl radical, or two alkyl radicals. More preferred alkylaminosulfonyl radicals are xe2x80x9clower alkylaminosulfonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.
The terms xe2x80x9cN-arylaminosulfonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminosulfonylxe2x80x9d denote sulfamyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are xe2x80x9clower N-alkyl-N-arylsulfonylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower N-alkyl-N-arylsulfonyl radicals having one to three carbon atoms. Examples of such lower N-alkyl-N-aryl-aminosulfonyl radicals include N-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl. Examples of such N-aryl-aminosulfonyl radicals include N-phenylaminosulfonyl, which may be optionally substituted on the phenyl ring.
The term xe2x80x9carylalkylaminosulfonylxe2x80x9d embraces aralkyl radicals as described above, attached to an aminosulfonyl radical. More preferred are lower arylalkylaminosulfonyl radicals having one to three carbon atoms.
The term xe2x80x9cheterocyclylaminosulfonylxe2x80x9d embraces heterocyclyl radicals as described above, attached to an aminosulfonyl radical.
The term xe2x80x9cheterocyclylsulfonylalkylxe2x80x9d embraces heterocyclyl radicals as described above, attached to an alkyl radical through a sulfonyl linker. More preferred are xe2x80x9clower heterocyclylsulfonylalkylxe2x80x9d wherein the alkyl portion is one to six carbons long. Even more preferred, the alkyl portions are 1-3 carbons long.
The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2H.
The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9caminocarbonylxe2x80x9d, denotes xe2x80x94(Cxe2x95x90O)xe2x80x94.
The term xe2x80x9caminocarbonylxe2x80x9d when used by itself or with other terms such as xe2x80x9caminocarbonylalkylxe2x80x9d, xe2x80x9cN-alkylaminocarbonylxe2x80x9d, xe2x80x9cN-arylaminocarbonylxe2x80x9d, xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d, xe2x80x9cN-alkyl-N-arylaminocarbonylxe2x80x9d, xe2x80x9cN-alkyl-N-hydroxyaminocarbonylxe2x80x9d and xe2x80x9cN-alkyl-N-hydroxyaminocarbonylalkylxe2x80x9d, denotes an amide group of the formula xe2x80x94C(xe2x95x90O)NH2.
The term xe2x80x9calkoxycarbonylxe2x80x9d denotes an ester group wherein the carbonyl group is substituted with an alkoxy radical, as described above. The carbonyl portion is the point of attachment. More preferred are xe2x80x9clower alkoxycarbonylxe2x80x9d having lower alkoxy radicals as described above attached to a carbonyl radical.
The terms xe2x80x9cN-alkylaminocarbonylxe2x80x9d and xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d denote aminocarbonyl radicals which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred are xe2x80x9clower alkylaminocarbonylxe2x80x9d having lower alkyl radicals as described above attached to an aminocarbonyl radical.
The term xe2x80x9calkylamino-alkylaminocarbonylxe2x80x9d denotes alkylaminocarbonyl radicals which have been substituted with an alkylamino radical. More preferred are xe2x80x9clower alkylamino-alkylaminocarbonylxe2x80x9d having lower alkyl radicals, as described above.
The terms xe2x80x9cN-arylaminocarbonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminocarbonylxe2x80x9d denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
The term xe2x80x9cheterocyclylalkylaminocarbonylxe2x80x9d denotes aminocarbonyl radicals substituted with a heterocyclylalkyl radical.
The term xe2x80x9cheterocyclylcarbonylxe2x80x9d denotes carbonyl radicals substituted with a heterocyclyl radical.
The term xe2x80x9caminoalkylxe2x80x9d embraces alkyl radicals substituted with amino radicals.
The term xe2x80x9calkylaminothiocarbonylxe2x80x9d denotes thioamide compounds comprising thiocarbonyl radicals (xe2x80x94C(S)xe2x80x94) which have been substituted with an alkylamino radicals. More preferred are xe2x80x9clower alkylaminothiocarbonylxe2x80x9d having lower alkyl radicals as described above.
The term xe2x80x9calkylaminoalkylxe2x80x9d embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term includes both mono- and di-substituted amines. Even more preferred are lower alkylaminoalkyl radicals having one to three carbon atoms.
The term xe2x80x9cheterocyclylalkylxe2x80x9d embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are xe2x80x9c5- or 6-membered heteroarylalkylxe2x80x9d radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9carylalkenylxe2x80x9d embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are xe2x80x9clower arylalkenylxe2x80x9d radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl. The aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9carylalkynylxe2x80x9d embraces aryl-substituted alkynyl radicals. Preferable arylalkynyl radicals are xe2x80x9clower arylalkynylxe2x80x9d radicals having aryl radicals attached to alkynyl radicals having two to six carbon atoms. Examples of such radicals include phenylethynyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of xe2x80x9calkylthioxe2x80x9d is methylthio, (CH3Sxe2x80x94).
The term xe2x80x9chaloalkylthioxe2x80x9d embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of xe2x80x9chaloalkylthioxe2x80x9d is trifluoromethylthio.
The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. More preferred are lower alkylsulfinyl radicals having one to three carbon atoms.
The term xe2x80x9carylsulfinylxe2x80x9d embraces radicals containing an aryl radical, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. Even more preferred are optionally substituted phenylsulfinyl radicals.
The term xe2x80x9chaloalkylsulfinylxe2x80x9d embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. Even more preferred are lower haloalkylsulfinyl radicals having one to three carbon atoms.
The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups which have been substituted with one alkyl radical and with two alkyl radicals, including terms xe2x80x9cN-alkylaminoxe2x80x9d and xe2x80x9cN,N-dialkylaminoxe2x80x9d. More preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable xe2x80x9calkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
The term xe2x80x9chydroxyalkylaminoxe2x80x9d denotes amino groups which have been substituted with a hydroxyalkyl radical, as defined above.
The term xe2x80x9cheterocyclylalkylaminoxe2x80x9d denotes alkylamino groups which have been substituted with a heterocyclyl radical, as defined above.
The tern xe2x80x9carylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical.
The term xe2x80x9cheteroarylaminoxe2x80x9d denotes amino groups which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The xe2x80x9cheteroarylaminoxe2x80x9d radicals may be further substituted on the heteroaryl ring portion of the radical.
The term xe2x80x9caralkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aralkyl radicals. More preferred are phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The xe2x80x9caralkylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical.
The terms xe2x80x9cN-alkyl-N-arylaminoxe2x80x9d and xe2x80x9cN-aralkyl-N-alkylaminoxe2x80x9d denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
The term xe2x80x9carylthioxe2x80x9d embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of xe2x80x9carylthioxe2x80x9d is phenylthio.
The term xe2x80x9caralkylthioxe2x80x9d embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-C1-C3-alkylthio radicals. An example of xe2x80x9caralkylthioxe2x80x9d is benzylthio.
The term xe2x80x9caryloxyxe2x80x9d embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
The term xe2x80x9cheterocyclyloxyxe2x80x9d embraces optionally substituted heterocyclyl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyrrolidinyloxy, piperidinyloxy, and pyridyloxy.
The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above.
The term xe2x80x9cheterocyclylalkoxyxe2x80x9d embraces oxy-containing heterocyclylalkyl radicals attached through an oxygen atom to other radicals. More preferred heterocyclyloxy radicals are xe2x80x9clower heterocyclyloxy xe2x80x9cradicals having optionally substituted 5-6 membered heterocyclyl radicals attached to lower alkoxy radical as described above.
The term xe2x80x9ccycloalkylxe2x80x9d includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopropyl, cyclopentyl and cyclohexyl.
The term xe2x80x9ccycloalkenylxe2x80x9d includes carbocyclic groups having one or more carbonxe2x80x94carbon double bonds. xe2x80x9cCycloalkenylxe2x80x9d and xe2x80x9ccycloalkyldienylxe2x80x9d compounds are included. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
The term xe2x80x9ccomprisingxe2x80x9d is meant to be open ended, including the indicated component but not excluding other elements.
The present invention preferably includes compounds that selectively inhibit GSK, CDK2 and/or CDK5.
The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of a cell proliferation or apoptosis mediated disease state, including those described previously. The compounds of the present invention are also useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of CDKs and other kinases. The compounds of the present invention are also useful in the manufacture of a medicament to treat neurological disorders.
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas I-VI in association with a least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a method of treating cell proliferative disorders, apoptosis mediated disorders, cancer, CDK mediated disorder or neurological disorders, in a subject, the method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formulas I-VI.
Combinations
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
The phrase xe2x80x9cco-therapyxe2x80x9d (or xe2x80x9ccombination-therapyxe2x80x9d), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents; or in the treatment of neurological disorders, such as with thrombolytic and anticoagulant agents, anti-inflammatory agents, NMDA inhibitors, antiparkinsonian agents, and inhibitors of lipid peroxidation.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of Formula I-VI may also be administered sequentially with known agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, at the same time with or after administration of the other agent.
Currently, standard treatment of primary tumors consists of surgical excision followed by either radiation or IV administered chemotherapy. The typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents or microtubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like. Experiments performed in in vivo animal models and in in vitro cell based assays have demonstrated that combining chemotherapeutic agents with cell cycle inhibitors, such as CDK inhibitors, typically results in either decreased rate of tumor growth or, in some cases, tumor regression. Combining chemotherapy with a CDK inhibitor typically results in an increased therapeutic index and lower levels of both agents are required. This ultimately results in a decrease in toxicity and an increase in efficacy.
Schwartz et al, Clin. Can. Res., 3,1467-1472 (1997) have demonstrated that combining the CDK inhibitor flavopiridol with mitomycin-C (DNA alkylating agent) resulted in an increased rate of apoptosis in gastric and breast cancer cells. Bible et al (Bible et al., Cancer Res., 57, 3375-3380 (1997) have also demonstrated therapeutic synergy exists between flavopiridol and paclitaxel, cytarabine, topotecan, doxorubicin, and etoposide (all standard chemotherapeutic agents) when tested in cell based assays using human non-small cell lung cancer cells. Preclinical models (cell culture) suggest that a cell cycle inhibitor potentiates the effect of a cytotoxic agent when administered after the chemotherapeutic agent. The chemotherapeutic agent will induce specific DNA/mitotic damage checkpoints in normal cells which in combination with a CDK inhibitor will cause a cell cycle arrest or cytostatic effect. In contrast, tumor cells will be driven into apoptosis or cell death when a chemotherapeutic agent and a CDK inhibitor are combined due to tumor cells attempting to activate defective DNA damage and cell cycle checkpoints. In addition, scheduling of a CDK inhibitor for clinical trials should include a rest period to allow the patients normal cells to recover and reduce the potential for cytotoxic side effects.
There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
A first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck and Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2xe2x80x2-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine protein kinase inhibitors, Taiho UFT and uricytin.
A second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SKandF-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
A third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SR1 International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of xcex1-carotene, xcex1-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICM compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B. cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SKandF-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.
Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celecoxib, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetraexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar.
Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as other kinase inhibitors including KDR inhibitors, p38 inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors, NSAID""s, SOD mimics or xcex1vxcex23 inhibitors.
Alternatively, the present compounds may also be used in co-therapies with other treatments for neurological treatments such as thrombolytic and anticoagulant agents including tPA, urokinase and inhibitors of platelet aggregation, p38 inhibitors, IL1ra, NMDA inhibitors, antiparkinsonian agents including carbidopa and levodopa, and inhibitors of lipid peroxidation, for example.
The present invention comprises a process for the preparation of a compound of Formula I-VI.
Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
Compounds of the present invention can possess, in general, tautomeric forms, which are included in the family of compounds in Formula I-VI.
Also included in the family of compounds of Formula I-VI are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-VI may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), -methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, xcex2-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I-VI include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I-VI.
Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as HCl, H2SO4 and H3PO4 and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
Additional examples of such salts can be found in Berge et al., J. Pharm. Sci., 66, 1 (1977).
The compounds of the invention can be synthesized according to the following procedures of Schemes 1-24, wherein the substituents are as defined for Formulas I-VI, above, except where further noted. 
Substituted pyridines can be prepared according to the method set out in Scheme 1. A mixture of halo-aniline 1, substituted amine and phenol is reacted, preferably at a temperature above RT and more preferably at temperature of about 150xc2x0 C., to yield the heterocyclyl derivative 2a or substituted amine derivative 2b. 
Substituted pyridines can be prepared according to the method set out in Scheme 2. A halopicolinic acid 3 is reacted with substituted amines (where Ra and Rb are H, alkyl, substituted alkyl, etc.) in the presence of chloroformate esters and base in a suitable solvent to form the halopyridyl amide derivatives 4. Preferably the reaction is at a temperature below RT, more preferably the reaction occurs at a temperature of about 0xc2x0 C. The halopyridyl amide 4 is dehalogenated, such as with NH4OH and Cu powder in an appropriate solvent, such as IpOH to form the aniline derivative 5. Preferably the reaction occurs at a temperature above RT, more preferably the reaction occurs at about 100xc2x0 C. The aniline derivative 5 is reduced, such as with LiAlH4 in Et2O to form the aminoalkyl derivative 6. 
Substituted 4-thiazolylurea compounds 12 are prepared from the corresponding nitrites 7 according to the method set out in Scheme 3. Substituted nitrites 7 are added to base at about RT and H2S is bubbled through the solution, to yield the thione 8. The thione 8 is combined with ethyl bromopyruvate and heated to form the thiazolyl carboxylate ester 9. Aqueous LiOH is heated with the ester 9 at a temperature above RT and preferably at reflux to give the thiazole carboxylic acid 10. Treatment of the substituted thiazolyl carboxylic acid 10 with base in a suitable solvent at about RT yields a salt. At about 0xc2x0 C., oxalyl chloride is added to a suspension of the salt in solvent followed by a catalytic amount of DMF. Afterwards, aqueous NaN3 is added to yield the thiazolyl carbonyl azide 11. The carbonyl azide 11 is added to substituted amines to form the thiazolyl urea compound 12. 
Substituted 4-thiazolylurea compounds 12 are prepared from either the corresponding nitrites 7a or the corresponding amides 7b according to the method set out in Scheme 3. Substituted nitrites 7a are added to base at about RT and H2S is bubbled through the solution, to yield the thione 8. Alternatively, substituted amides 7b are treated with P2S5, NaCO3 in THF and heated to give 8. The thione 8 is combined with ethyl bromopyruvate and heated to form the thiazolyl carboxylate ester 9. Aqueous LiOH is heated with the ester 9 at a temperature above RT and preferably at reflux to give the thiazole carboxylic acid 10. Treatment of the substituted thiazolyl carboxylic acid 10 with base in a suitable solvent at about RT yields a salt. At about 0xc2x0 C., oxalyl chloride is added to a suspension of the salt in solvent followed by a catalytic amount of DMF. Afterwards, aqueous NaN3 is added to yield the thiazolyl carbonyl azide 11. The carbonyl azide 11 is added to substituted amines to form the thiazolyl urea compound 12. 
Substituted 4-thiazolylurea compounds 27 are prepared from the corresponding pyridines 24 according to the method set out in Scheme 58. Reductive amination with an amine (including nitrogen-containing heterocycles) and 6-bromo-2-pyridinecarboxaldehyde 24, is achieved such as in a halocarbon solvent such as dichloromethane, in the presence of NaBH(OAc)3 and acid, such as AcOH, to give 2-aminomethyl-6-bromo-pyridine 25. The 2-aminomethyl-6-bromo-pyridine 25 is aminated, such as with NH4OH in the presence of Cu powder, such as in the presence of an alcohol solvent, at a temperature above about 50xc2x0 C. and preferably at about 100xc2x0 C., such as in a sealed tube to give the corresponding aniline 6. A substituted thiazolylcarbonylazide, such as in dry hydrocarbon solvent such as toluene is heated at a temperature above about 50xc2x0 C. and preferably above about 85xc2x0 C. and reacted with the aniline 6 to give the 4-thiazolylurea compounds 27.
Alternatively, the aniline 6 can be coupled with thiazolyl carboxylic acid, such as with DPPA in the presence of base, such as TEA, and molecular sieves in a solvent like THF. The reaction can be heated at a temperature above about 50xc2x0 C. and preferably at about reflux yielding the 4-thiazolylurea compounds 27. 
Thiazolyl carboxylic acid 31 (especially appropriate where Rxe2x80x2 is a sulfonamide or amine) are prepared from the corresponding benzonitriles 28 as described in Scheme 9. H2S is added to the substituted 4-cyanobenzene 28 in the presence of base, such as Et3N to af ford the thiobenzamide 29. The thiobenzamide 29 is reacted with ethyl bromopyruvate, such as in an alcohol solvent like EtOH, at a temperature greater than about 50xc2x0 C., and preferably at about 75xc2x0 C. to give the thiazolyl ester 30. The thiazolyl ester 30 is hydrolyzed, such as with LiOH monohydrate in an alcohol like aqueous MeOH, at a temperature greater than about 50xc2x0 C., and preferably at about 75xc2x0 C., to provide the acid 31. The acid can be used similar to that described in Scheme 8. 
Substituted anilines 35 are prepared from the corresponding methyl compounds 32 as described in Scheme 10. 2-Amino-3-picoline is protected such as with solid carboethoxyphthalimide and base like TEA to provide the phthalimide (Phth) protected aniline 32. The protected 3-methylaniline is brominated, such as with NBS and AIBN at a temperature above 50  C. and preferably at about reflux. Additional AIBN and NBS may be needed to push the reaction to completeness. The dibromomethyl aniline 34 is reacted with an amine, preferably a secondary amine such as substituted or unsubstituted nitrogen containing heterocyclics like piperidines and piperazines, in the presence of acid like glacial AcOH and halocarbon solvent such as CH2Cl2. Treatment with NaBH(OAc)3 provided the protected substituted methyl compound which is deported, such as by treatment with hydrazine monohydrate at a temperature greater than about 50xc2x0 C., and preferably at reflux to provide the substituted aniline 35. 
Substituted anilines 39 are prepared from the corresponding methyl compounds 36 as described in Scheme 11. N-Pivaloyl-2-amino-6-bromomethylpyridine 37 is prepared by the method of M. V. Papadopoulou, et al. (J. Heterocyclic Chem., 1995, 32, 675-681). The protected bromomethyl compound is treated with an alcohol or amine in the presence of base, such as NaH to yield the corresponding ether or amino alkyl compounds 38 (where X is O or N). The protected ether or amino alkyl compounds 38 is treated with base, such as in methanolic KOH and warmed to a temperature greater than about RT, and preferably at about 55xc2x0 C., to provide the substituted anilines 39. 
Thiazolylcarbonylazides 43 are prepared as described in Scheme 12. Bromothiazole is coupled with an aryl alcohol, such as phenol, at a temperature greater than about 100xc2x0 C., and preferably at about 180xc2x0 C., to provide the phenoxy compound 41. The thiazolyl ester 41 is hydrolyzed, such as with LiOH monohydrate in an alcohol like aqueous MeOH, at a temperature greater than about 50xc2x0 C., and preferably at about 75xc2x0 C., to provide the acid 42. Acid 42 is added to ethyl chloroformate and NaN3, in the presence of base such as TEA, to provide the azide 43, which can be used as described in Scheme 8. 
Pyridyl-2-thiazoles 47 are prepared as described in Scheme 13. 4-Chloronicotinamide 44 is converted to the thioamide 45 such as be treatment with P2S5, in the presence of base, such as Na2CO3, at a temperature greater than about 50xc2x0 C., and preferably at about reflux. The thioamide 45 is converted to the thiazole ester 46 by treatment with bromoethylpyruvate and heating at a temperature greater than about 50xc2x0 C., and preferably at about reflux. The ethyl ester is transesterified to the methyl ester with treatment with base, such as NaOMe. Further addition of base and heating at a temperature greater than about 50xc2x0 C., and preferably at about reflux, hydrolyzed the ester to the acid. Additional NaOMe, in the presence of MeOH, and heating at a temperature greater than about 50xc2x0 C., and preferably at about reflux, provided the methoxy substituted pyridine compound 47. Use of other bases and alcohols provide alternative alkoxy substituted compounds. 
Protected aminoalkyl pyridines 53 are prepared from the 2-amino-6-methylpyridine 48 as described in Scheme 14. The amino group of 2-amino-6-methylpyridine 48 is protected, such as with BOC and normal coupling chemistry, such as with Boc2O and base, like TEA, and DMAP. The protected compound 49 is brominated such as with NBS and AIBN and heating at a temperature greater than about 50xc2x0 C., and preferably at reflux to provide the bromomethyl derivative 50. The bromomethyl derivative 50 is converted to the cyanomethyl compound 51 such as with treatment with NaCN in the presence of alcohol solvent such as EtOH, and heating at a temperature greater than about 50xc2x0 C., and preferably at reflux. The cyanomethyl compound 51 is hydrogenated to the aminoethyl derivative 52 such as with hydrogen in the presence of Pd(OH)2/C at a temperature about RT. The aminoethyl derivative 52 is converted to the di-protected compound such as with phthalic anhydride and heating at a temperature between RT and about 70xc2x0 C. Upon on treatment with strong acid, such as TFA, provides the 2-aminopyridyl compound 53. 
Compounds of Formula I are prepared as described in Scheme 15. Phthalimidylethyl compounds 54 are prepared from the coupling of compounds prepared similar to those described in Scheme 14 and thiazolyl acylazides as described in Scheme 8. Treatment of 54 with hydrazine hydrate and heating at a temperature greater than about 50xc2x0 C., and preferably at ref lux, provides the aminoethyl derivatives 55. Alkylation of the amine 55, such as with paraformaldehyde and NaBH(OAc)3 in a haloalkyl solvent, such as CH2Cl2 provides the dimethylamine 56. 
Compounds of Formula I (where R7 is optionally substituted phenyl) are prepared as described in Scheme 16. The 2-aminothiazole 57 is prepared from thiourea and ethyl bromopyruvate, in an alcoholic solvent like ethanol, at a temperature greater than about RT, and preferably at about 45xc2x0 C. Treatment of the ethyl 2-aminothiazole-4-carboxylate with HBr, NaNO2, CuBr and heating at a temperature greater than about 50xc2x0 C., and preferably at about 70xc2x0 C., provides the bromo thiazole ester. Hydrolysis of the ester, such as with aqueous NaOH and alcohol, such as EtOH and heating at a temperature greater than about 50xc2x0 C., and preferably at reflux provides the bromothiazole acid 58. Coupling with substituted amines, similar to that described in Scheme 8, provides the 2-bromothiazolyl urea 59. Suzuki coupling of 2-bromothiazolyl urea 59 with phenyl boronic acids provides the compounds where R7 is optionally substituted phenyl 60. 
Substituted aminopyridines 65 are prepared by the method described in Scheme 17. 2-[(6-Bromo-2-pyridyl)methyl]aminopropan-1-ol 61 is protected such as with Boc with di-tert-butyldicarbonate in dry CH2Cl2. Conversion 10 to the aldehyde 63 is accomplished by treatment with oxalyl chloride (in CH2Cl2), and DMSO at a temperature below RT, preferably below about xe2x88x9223xc2x0 C. and more preferably at about xe2x88x9263xc2x0 C. Addition of bas,e such as DEA, to the aldehyde 63, and heating to reflux in a Dean-Stark trap, followed by the 15 addition of a solution of NaBH(OAc)3 in acid such as AcOH at RT provided the aminoalkylxe2x80x94aminoalkyl derivative 64. The aminopyridine 65 is prepared as described above. 
Substituted aminopyridines 69 are prepared by the method described in Scheme 18. 2-Chloroisonicotinic acid 66 is coupled with an amine, such as with standard coupling chemistry, for example with a carbodiimide, such as EDCI, in the presence of base, such as DIEA, in an appropriate solvent such as CH2Cl2, to provide amide 67 where Ra is alkyl, aryl or together with the nitrogen atom forms a heterocyclic ring. The nicotinamide is aminated, such as with ammonium hydroxide in the presence of a metal such as Cu in an appropriate solvent such as IpOH and heated at a temperature above RT, preferably above about 50xc2x0 C., more preferably at about 100xc2x0 C., preferably in a sealed tub vessel, to form the amino-nicotinamide 68. The amino-nicotinamide 68 is reduced, such as with LAH, at a temperature above RT, preferably above about 50  C., more preferably at about reflux, to form the methylamine 69. 
Substituted alkynyl thiazoles 72 are prepared by the method outlined in Scheme 19 where Rb is cycloalkyl, alkyl and the like. Bromothiazole 71 is substituted with the alkyne 70, such as in the presence of Pd(PhCN)2Cl2, CuI2 and t-Bu3P, and base such as DEA, in an appropriate solvent such as dioxane. The reaction temperature is maintained at about RT, to form the alkynyl thiazoles 72. 
Thiazolylazides 76 are prepared by the method shown in Scheme 20. 2-Amino-thiazole-4-carboxylic acid ester hydrobromide is basified, such as with a saturated solution of NaHCO3 to provide the free base. The free base is subsequently halogenated, such as with a metal halide, preferably NaCl or NaBr, in the presence of acid, preferably H2SO4, more preferably 9M H2SO4, and CuSO4 and NaNO2 at a temperature of about RT to form the halothiazole. The 2-halothiazole-4-carboxylic acid ester is hydrolyzed with a base, such as LIOH, at a temperature above RT, preferably above about 50xc2x0 C., more preferably about 65xc2x0 C., to form acid 75. The azido-thiazole 76 is prepared from the 2-halo-thiazole-4-carboxylic acid 75 in the presence of base, such as TEA, ethyl chloroformate and sodium azide at a temperature about RT. 
Substituted bromo-pyridines 78 and 79 are prepared from dibromo-pyridine 77 as described in Scheme 21. 2,6-Dibromopyridine 77 is reacted with an aminoalcohol in an appropriate solvent, such as THF, at a temperature above RT, preferably at a temperature above about 50xc2x0 C., more preferably at reflux, to form the amino pyridine. The alcoholamino-pyridine is coupled with 3,4-dihydro-2H-pyran such as with TsOH in the presence of an appropriate solvent, such as CH2Cl2 at a temperature of about RT, to form the pyran substituted pyridine 78.
D-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester is treated with a strong base, preferably NaH, at a temperature about RT, then 2,6-dibromopyridine 77 is added and reacted at a temperature above RT, preferably at a temperature above about 50xc2x0 C., more preferably at about 90xc2x0 C. to form the pyrrolidinyl ether 79. 
2-(Piperidinyl)pyridines 83 are prepared as described in Scheme 22. Strong base, such as n-BuLi, in a solvent such as dry THF, is added to dibromopyridine 77 at a temperature less than RT, preferably below about xe2x88x9250xc2x0 C., more preferably at about xe2x88x9270xc2x0 C. 4-Methylpiperidone is added to form the 4-hydroxy-piperidine 80 at a temperature less than RT, preferably below about xe2x88x9250xc2x0 C., more preferably at about xe2x88x9270xc2x0 C. The 4-hydroxy piperidine 80 is hydrated, such as with strong acid, preferably H2SO4, at a temperature above RT, preferably above 750C, more preferably at about 100  C., to form the tetrahydro-bipyridine 81. The 2-bromo-pyridine 81 is aminated, such as with NH4OH, in the presence of Cu powder at a temperature above RT, preferably above about 75xc2x0 C., more preferably at about 100xc2x0 C., to form the amino-pyridine 82. Preferably the reaction is run in a sealed tube. The 1xe2x80x2,2,3xe2x80x2,6xe2x80x2-tetrahdyro-[2,4xe2x80x2]bipyridinyl-6-ylamine is hydrogenated, such as with H2 in the presence of Pd(OH)2/C, at a temperature of about RT, to form the piperidinyl pyridine 83. 
Thiazolyl indazoles 87 can be prepared from anilines as outlined in Scheme 23. Similar to the method of J. Sun, et al, J. Org. Chem., 1997, p. 5627, protected 1H-indazole-5-carbonitrile 85 is prepared from 4-amino-3-methylbenzo-nitrile 84 in the presence of acetic anhydride, and KOAc in an appropriate solvent such as CHCl3. The protected 1H-indazole-5-carbothioic acid amide 85 is prepared from the carbonitrile 84 by treatment with H2S gas in the presence of base, such as Et3N and solvent, such as THF, at a temperature below RT, preferably at about 0xc2x0 C. The amide 86 is added to a diketo compound, such as ethylbromopyruvate at a temperature above RT, preferably above about 50xc2x0 C., more preferably at reflux, in an appropriate solvent such as EtOH, to form the thiazolyl indazole ester. The ester is hydrolyzed with base, such as with LiOH at a temperature of about RT to yield the free acid 87. Additionally, the indazole may be acylated, such as with Ac2O. 
Disubstituted aminopyridines 91 can be prepared from the corresponding acids 88, where Rc is heterocyclyl, as described in Scheme 24. Carboxylic acid or the corresponding ester is reduced, such as with BH3-THF solution in a solvent, such as in dry THF, at a temperature of about RT, to form the alcohols 89. Oxalyl chloride and DMSO in a solvent such as dry CH2Cl2, is treated with the alcohol 89 in the presence of base, such as TEA at a temperature of about RT, to form the aldehyde 90. The aldehyde 90 is coupled with an heteroaryl group, such as diaminopyridine in a solvent such as dry CH2Cl2, via reductive amination for example in the presence of NaBH(OAc)3, piperidine and HOAc, at a temperature above RT, preferably at about 40xc2x0 C., to form the substituted amino pyridine 91.
N-Oxides can be obtained in a known matter by reacting a compound of Formula I-VI with hydrogen peroxide or a peracid, e.g. 3-chloroperoxy-benzoic acid, in an inert solvent, e.g. CH2Cl2, at a temperature between about xe2x88x9210 to about 35xc2x0 C., such as about 0xc2x0 C. to about RT.
In the preparation of starting materials, existing functional groups, for example carboxy, hydroxy, amino, or mercapto, which do not participate in the reaction should, if necessary, be protected. Such protecting groups are those or similar to those usually used in the synthesis of peptide compounds, cephalosporins, penicillins, nucleic acid derivatives or sugars. Preferred protecting groups, their introduction and their removal are described above or in the examples.
The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves ready removal, i.e. without undesired secondary reactions, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. One skilled in the art knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter.
The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference works, such as J. F. W. McOmie, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, London and New York 1973, in T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, New York 1981, in xe2x80x9cThe Peptidesxe2x80x9d; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in xe2x80x9cMethoden der organischen Chemiexe2x80x9d (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H. -D. Jakubke and H. Jescheit, xe2x80x9cAminosauren, Peptide, Proteinexe2x80x9d (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, xe2x80x9cChemie der Kohlenhydrate: Monosaccharide und Derivatexe2x80x9d (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.
In the additional process steps, carried out as desired, functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned above under xe2x80x9cprotecting groupsxe2x80x9d. The protecting groups are then wholly or partly removed according to one of the methods described there.
In certain cases, typically in hydrogenation processes, it is possible to achieve stereoselective reactions, allowing for example easier recovery of individual isomers.
The solvents from which those can be selected which are suitable for the reaction in question include, for example, water, esters, typically lower alkyl-lower alkanoates, e.g EtOAc, ethers, typically aliphatic ethers, e.g. Et2O, or cyclic ethers, e.g. THF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH or 1-propanol or iPrOH, nitrites, typically CH3CN, halogenated hydrocarbons, typically CH2Cl2, acid amides, typically DMF, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g. AcOH, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g. Ac2O, cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
The invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ. In the preferred embodiment, one starts from those starting materials which lead to the compounds described above as preferred.
The compounds of Formula I-VI, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In the preferred embodiment, such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
Starting materials of the invention, are known, are commercially available, or can be synthesized in analogy to or according to methods that are known in the art.
All remaining starting materials are known, capable of being prepared according to known processes, or commercially obtainable; in particular, they can be prepared using processes as described above or as in the examples.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below: 
The invention expressly includes all tautomeric forms of the compounds described herein.
The compounds may also occur in cis- or trans- or E- or Z-double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Substituents on ring moieties (e.g., phenyl, thiazolyl, etc.) may be attached to specific atoms, whereby they a re intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen).
The compounds of this invention may contain heterocyclic ring systems attached to another ring system. Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
A compound of any of the formulas delineated herein may be synthesized according to any of the processes delineated herein. In the processes delineated herein, the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necessary. The processes may further comprise use of appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K2CO3, and the like), catalysts, and salt forms of the above. The intermediates may be isolated or carried on in situ, with or without purification. Purification methods are known in the art and include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed (xe2x80x9cSMBxe2x80x9d)), extraction, distillation, trituration, reverse phase HPLC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction. Additionally, the compounds can be produced metabolically.
As can be appreciated by one skilled in the art, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. Greene and P. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser""s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995); P. Lopez et al., Synthesis 2, 186 (1998); A. Mikhalev, et al., Khim. Geterotsikl Soedin, 5, 697 (1997); M. Fernandez, et al., Synthesis, 11, 1362 (1995); P. Desos, et al., J. Med. Chem, 39, 197 (1996); G. Timari, et al., Synlett, 9, 1067 (1997); Y. Tagawa, et al., J. Heterocycl. Chem., 34, 1677 (1997); A. Fuerstner, et al., Chem. Sci. 50, 326 (1995); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2nd Ed. (2001); and WO01/132658.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I-VI. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.
The following abbreviations are used:
Preparation A: 2-Amino-6-morpholinopyridine:
A mixture of 2-chloro-6-aminopyridine (200 mg, 1.49 mmol), morpholine (326 mg, 3.75 mmol) and phenol (2 g) was heated at 150xc2x0 C. for 20 h. After cooling to RT, 3N NaOH (10 mL) was added and the mixture was extracted with EtOAc (3xc3x9750 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel (1:10 MeOH/CH2Cl2) to afford the morpholino derivative as an amber oil. MS m/z: 180 (M+1).
Preparation B: 2-Bromo-6-N,N-diethylamidopyridine:
Ethyl chloroformate (1.76 g, 16.3 mmol) was added dropwise to a mixture of 6-bromopicolinic acid (3 g, 14.8 mmol) and Et3N (1.8 g, 17.8 mmol) in THF (150 mL) at 0xc2x0 C. After the mixture was stirred for 1 h, DEA (1.3 g, 17.8 mmol) was added slowly to the mixture at 0xc2x0 C. The resulting mixture was stirred at RT for 5 h. H2O (200 mL) was added and the mixture was extracted with EtOAc (3xc3x97120 mL). The combined organic layers were washed with 1N NaOH and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford 2-bromo-6-N,N-diethylamidopyridine as an amber oil. MS m/z: 259 (M+1).
Preparation C: 2-Amino-6-N,N-diethylamidopyridine:
A mixture of 2-bromo-6-N,N-diethylamidopyridine (3.5 g), 50 mL of 37% NH4OH and 0.8 g of Cu powder in 40 mL of IpOH was heated at 100xc2x0 C. in sealed tube for 20 h. After cooling to RT, brine was added and the mixture was extracted with EtOAc (3xc3x97120 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the amino derivative as a light amber solid. MS m/z: 194 (M+1).
Preparation D: 2-Amino-6-N,N-diethylaminomethylpyridine:
To a solution of 2-amino-6-N,N-diethylamidopyridine (2.2 g, 11.4 mmol) in 200 mL of THF was added slowly 34.2 mL of LiAlH4 (1.3 g, 34.2 mmol) solution in Et2O at 0xc2x0 C. The resulting mixture was heated at reflux for 6 h. After cooling to 0xc2x0 C., 2 mL of H2O, 1.3 mL of 15% NaOH and 7.5 mL of H2O was added to the mixture sequentially. After stirring for 2 h at RT, the mixture was filtered through Celite(copyright). The filtrate was concentrated and purified by chromatography on silica gel (1:10 MeOH(NH3)/CH2Cl2) to afford the aminomethyl compound as an amber oil. MS m/z: 180 (M+1).
Preparation E: 2-Amino-6-(N-methylpiperazinyl)pyridine:
A mixture of 2-bromo-6-aminopyridine (3 g, 17.34 mmol), 1-methylpiperizine (2.3 g, 22.54 mmol) and Cu powder (0.5 g, 7.87 mmol) in 5 mL of 2,4-diethylphenol was heated at 150xc2x0 C. for 20 h. After cooling to RT, 3N HCl (30 mL) was added and the mixture was extracted with Et2O (2xc3x97100 mL). The aqueous layer was basified with concentrated NH4OH to pH greater than 10 and then extracted with EtOAc (3xc3x97100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel (1:10 MeOH(NH3)/CH2Cl2) to afford the piperazinyl compound as a light amber solid. MS m/z: 193 (M+1).
Preparation F: 2-Amino-6-(4-morpholino)propylamino-pyridine:
A mixture of 2-bromo-6-aminopyridine (0.5 g, 2.92 mmol), 4-(3-aminopropyl)morpholine (1.5 g 10.42 mmol) and Cu powder (0.6 g, 9.52 mmol) in 15 mL of IpOH and 5 mL of H2O was heated at 100xc2x0 C. in a sealed tube for 24 h. After cooling to RT, water was added and the mixture was extracted with EtOAc (3xc3x9750 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel (1:10 MeOH(NH3)/CH2Cl2) to afford the morpholino compound as an amber oil. MS m/z: 237 (M+1).
Preparation G: 2-Amino-6-(2-N,N-dimethylamino) ethylaminopyridine:
A mixture of 2-bromo-6-aminopyridine (0.3 g, 1.17 mmol), N,N-dimethylethylenediamine (1 g, 11.36 mmol) and Cu powder (0.74 g, 11.7 mmol) in 30 mL of IpOH was heated at 100xc2x0 C. in sealed tube for 20 h. After cooling to RT, H2O was added and the mixture was extracted with EtOAc (3xc3x9750 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel (1:10 MeOH (NH3)/CH2Cl2) to afford the compound as an oil. MS m/z: 181 (M+1)
Preparation H: Amino-2-pyridylmethane-1-thione:
2-Cyanopyridine (2.6 g, 0.025 mol) was added to a solution of TEA (5.5 mL) and dry pyridine (50 mL) at RT. H2S was bubbled through the solution for 1 h. Afterwards, H2O (150 mL) was added and the mixture was extracted with EtOAc (3xc3x9750 mL). The EtOAc extracts were dried over Na2SO4, filtered, and the solvent was removed under vacuum. The resulting residue was purified by column chromatography eluting with hexanes:EtOAc (4:1) to give amino-2-pyridylmethane-1-thione as a light yellow solid. GC/MS m/z: 139 (M+H); GC Retention time: 7.93 min.
Preparation I: 2-(2-Pyridinyl)thiazole-4-carboxylic acid:
Amino-2-pyridylmethane-1-thione (1.88 g, 0.0136 mol), ethyl bromopyruvate (1.80 mL, 0.0143 mol) and EtOH (30 mL) were combined and heated to reflux. GC/MS of reaction mixture after 3 h showed total consumption of the starting materials. After cooling to RT, the solvent was removed under vacuum resulting in a dark brown oil (GC/MS m/z: 235 (M+H); GC Retention time: 10.69 min). The material was taken up in MeOH (20 mL), 1.0M LiOH-H2O (20 mL) was added and the mixture was heated to 100xc2x0 C. for 14 h. After cooling to RT, the excess MeOH was evaporated and the resulting brown solid filtered. The material was washed with a minimum of H2O and dried in vacuo to give the thiazole as a brown solid.
Preparation J: 2-(4-Pyridinyl)-4-thiazolylcarbonylazide:
To a suspension of 2-(4-pyridinyl)-4-thiazolyl carboxylic acid (Maybridge Chem., 6.0 g, 29.1 mmol) in 150 mL MeOH at RT was added NaOH (1.28 g, 32.0 mmol) and the mixture was stirred at RT for 45 min. The reaction mixture was concentrated in vacuo then dried under high vacuum for 60 h (overnight drying is a minimum). The crude salt was suspended in 150 mL of CH2Cl2 and cooled in an ice bath. Oxalyl chloride (2.8 mL) was added slowly to the suspension followed by a catalytic amount of DMF (0.2 mL). The mixture was stirred for 2 h and warmed to RT. The reaction was cooled in an ice bath and a solution of NaN3 (2.27 g) in water (90 mL) was added and stirring was continued for 3 h. The reaction mixture was diluted with water (90 mL) and extracted with CH2Cl2 (3xc3x9775 mL). The combined organic layers were filtered through Celite(copyright) (xcx9c12 g) washed with 90 mL brine, dried with MgSO4 and concentrated in vacuo. Drying the crude compound on the vacuum line afforded the azido derivative as a light brown solid. MS m/z: 204.5 (Mxe2x88x92N2+H).
Preparation K: 2-(3-Pyridinyl)-4-thiazolylcarbonylazide:
In a manner similar to that described for the preparation of 2-(4-pyridinyl)-4-thiazolylcarbonylazide, 6.0 g of 2-(3-pyridinyl)-4-thiazolylcarboxylic acid was treated successively with NaOH, oxalyl chloride and a solution of NaN3 in water to give the 3-pyridinylazide as a pale brown solid. MS m/z: 204.5 (Mxe2x88x92N2+H)
Preparation L: 2-(2-Pyridinyl)-4-thiazolylcarbonylazide:
In a manner similar to that described for the preparation of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide, 2-(2-pyridinyl)-4-thiazolylcarboxylic acid (1.0 g)was treated successively with NaOH, oxalyl chloride and a solution of NaN3 in water to give the 2-pyridinyl azide as a pale brown solid: m.p. 112-114xc2x0 C. MS m/z: 232 (M+H).
Preparation M: 2-Phenyl-4-thiazolylcarbonylazide:
In a manner similar to that described for the preparation of 2-(4-pyridinyl)-4-thiazolylcarbonyl-azide, 1.0 g of 2-phenyl-4-thiazolylcarboxylic acid was treated successively with NaOH, oxalyl chloride and a solution of NaN3 in water to give the phenylazide as an off white solid. MS m/z: 203.5 (Mxe2x88x92N2+H).
Preparation N: 4-(6-Bromo-pyridin-2-ylmethyl)-morpholine
To a stirred solution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) in dichloroethane (10 mL) was added morpholine (0.14 mL, 1.62 mmol) followed by NaBH(OAc)3 (458 mg, 2.16 mmol) and AcOH (0.25 mL, 4.32 mmol). The resulting mixture was stirred at RT for 12 h. The reaction was quenched with 2M Na2CO3 solution and stirred 1 h. The mixture was poured into Et2O and washed with 2 M Na2CO3 solution. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo to give 2-bromo-6-morpholinyl-methylpyridine as a white solid. MS m/z: 256.9 (M+H).
The following compounds were prepared in a manner similar to that described above:
1] 1-(6-Bromopyridin-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester, as a pale yellow solid, was prepared in a manner similar to that described in General Preparation N [6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.16 mmol) was added to ethyl isonipecotate (0.5 mL, 3.24 mmol) in dry CH2Cl2 (10 mL)]. MS m/z: 327.0 (M+H). Calc""d for C14H19BrN2O2: 326.90.
2] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.16 mmol) was added L-leucinol (0.42 mL, 3.24 mmol) in dry CH2Cl2 (10 mL) to give 2-[(6-bromo-pyridin-2-ylmethyl)-amino]-4-methyl-pentan-1-ol as brown solid. MS m/z: 287.6 (M+H). Calc""d for Cl2H19BrN2O: 287.2.
3] To 6-bromo-2-pyridinecarboxaldehyde (500 mg, 2.69 mmol) was added 1,4-dioxa-8-azaspiro-[4,5]-decane (0.5 mL, 4.03 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-(4-ethoxyacetal)-piperidinylmethylpyridine as white solid. MS m/z: 313 (M+H). Calc""d for C13H17BrN2O2: 313.2.
4] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 3,5-dimethylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-(3,5-dimethyl)piperidinylmethyl pyridine as white solid. MS m/z: 283.2 (M+H). Calc""d for C13H19BrN2: 283.2
5] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(4-methyl)piperidinylmethyl]pyridine as a white solid. MS m/z: 269.4 (M+H). Calc""d for C12H17BrN2: 269.18.
6] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 2-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(2-methylpiperidinyl)methyl]pyridine as a pale yellow solid. MS m/z: 269.1(M+H). Calc""d for C12H17BrN2: 269.18.
7] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-(1-pyrrolidinyl)-piperidine (500 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-[4-(1-pyrrolidinyl)-piperidinylmethyl]pyridine as a pale yellow solid. MS m/z: 326.1(M+2H). Calc""d for C15H22BrN3: 324.26.
8] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 3-hydroxypiperidine (326 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-(3-hydroxypiperidinyl)methyl pyridine as pale yellow solid. MS m/z: 271.2 (M+H). Calc""d for C11H15BrN2O: 271.15.
9] To 6-bromo-2-pyridinecarboxaldehyde (300 mg, 1.62 mmol) was added hexamethyleneimine (0.27 mL, 2.43 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-(azaperhydroepinylmethyl)pyridine as a white solid. MS m/z: 270.3(M+H). Calc""d for C12H17BrN2: 269.18.
10] To 4-hydroxypiperidine (143 mg, 1.41 mmol) was added a solution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) to give 2-bromo-6-[(4-hydroxypiperidyl)methyl]-pyridine as a white -solid. MS m/z: 271.0 (M+H). Calc""d for C11H15BrN2Oxe2x80x94271.15.
11] 3-Hydroxypropylamine (0.15 mL, 2.02 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (250 mg, 1.35 mmol) to give 2-bromo-6-[(3-hydroxypropyl)amino]-methylpyridine as a white solid. MS m/z: 245.1 (M+H). Calc""d for C11H13BrN2Oxe2x80x94245.19.
12] Ethyl(piperidyl-3-carboxylate (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-3-carboxylate as a colorless oil. MS m/z: 327.1 (M+H). Calc""d for C14H19BrN2O2xe2x80x94327.22.
13] Ethyl (2-piperidyl)carboxylate (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-2-carboxylate as a colorless oil). MS m/z: 327.1 (M+H). Calc""d for C14H1gBrN2O2xe2x80x94327.22.
14] N,N-Diethylcarbamoyl-piperidine-3-carboxamide (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give N,N-diethyl 1-(6-bromopyridin-2-ylmethyl)piperidine-3-carboxamide as a colorless oil. MS m/z: 354.1 (M+H). Calc""d for C16H24BrN3Oxe2x80x94354.29.
15] 2-Pyrrolidine carboxylic acid (0.68 g, 5.92 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (1.0 g, 5.38 mmol) to give 1-(6-bromopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid as a white solid. MS m/z: 285.1 (M+H). Calc""d for C11H13BrN2O2xe2x80x94285.14.
16] 3-Methylpiperidine (0.33 mL, 2.8 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (350 mg, 1.88 mmol) to give 2-bromo-6-[(3-methylpiperidyl)methyl]pyridine as a white solid.
MS m/z: 269.1 (M+H). Calc""d for C12H17BrN2xe2x80x94269.18.
Preparation O: 6-Morpholin-4-ylmethyl-pyridin-2-ylamine
NH4OH (2 mL) and Cu powder (10 mg, 0.15 mmol) were added to a solution of 2-bromo-6-morpholinylpyridine (231 mg, 0.90 mmol) in IpOH (5 mL) and the resulting mixture was heated at 100xc2x0 C. for 36 h in a sealed tube. After cooling to RT, the mixture was partitioned between H2O and EtOAc. The organic layer was collected, washed with brine, and dried over Na2SO4. Concentration in vacuo gave the tilted compound as a pale yellow solid. MS m/z: 194.1 (M+H).
The following amines were prepared from the corresponding bromo compounds (prepared by Preparation N) in a manner similar to that described in General Preparation O:
1] 1-(6-amino-pyridin-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester as brown liquid. MS m/z: 264.2 (M+H). Calc""d for C14H21N3O2: 263.34.
2] 2-amino-6-[Nxe2x80x2-tert-butoxycarbonyl-Nxe2x80x2-2-(1-hydroxy-4-methyl)pentylamino]methylpyridine as a brown -liquid. MS m/z: 324.3 (M+H). Calc""d for C17H29N3O3: 323.2.
3] 2-amino-6-(4-ethoxyacetalpiperidinyl)-methylpyridine as a white solid. MS m/z: 250 (M+2H). Calc""d for C13H19N3O2: 249.1.
4] 2-Amino-6-(3,5-dimethylpiperidinyl)methyl-pyridine as a yellow solid. MS m/z: 220.3 (M+H). Calc""d for C13H21N3: 219.
5] 2-Amino-6-(4-methylpiperidinyl)methylpyridine as a yellow solid. MS m/z: 206.3 (M+H). Calc""d for C12H19N3: 205.28.
6] 2-Amino-6-(2-methylpiperidinyl)methylpyridine as a yellow liquid. MS m/z: 206.3 (M+H). Calc""d for C12H19N3: 205.28.
7] 2-Amino-6-[[4-(1-pyrrolidinyl)piperidinyl]methyl]-pyridine as a brown liquid. MS m/z: 261.1 (M+2H). Calc""d for C12H19N3: 260.
8] 2-Amino-6-(3-hydroxypiperidinyl)methylpyridine as a yellow liquid. MS m/z: 410.9 (M+H). Calc""d for C11H17N30: 410.5.
9] 2-Amino-6-(azaperhydroepinylmethyl)pyridine as a white solid. MS m/z: 206.1 (M+H). Calc""d for C12H19N3: 205.32.
10] 2-Amino-6-[(4-hydroxypiperidyl)methyl]pyridine as a pale yellow oil. MS m/z: 208.1 (M+H). Calc""d for C11H17N3Oxe2x80x94207.27.
11] 2-Amino-6-[(N-tert-butoxycarbonyl-N-(3-hydroxypropyl)amino]methylpyridine as a pale yellow oil. MS m/z: 282.3 (M+H). Calc""d for C14H23N3O3xe2x80x94281.35.
12] Ethyl 1-[(6-aminopyridin-2-yl)methyl]-piperidine-3-carboxylate as a pale yellow oil. MS m/z: 264.1 (M+H). Calc""d for C14H21N3O2xe2x80x94263.34.
13] Ethyl 1-[(6-aminopyridin-2-yl)methyl]-piperidine-2-carboxylate as a pale yellow oil. MS m/z: 264.1 (M+H). Calc""d for C14H21N3O2xe2x80x94263.34.
14] N,N-Diethyl 1-(6-aminopyridin-2-ylmethyl)-piperidine-3-carboxamide as a pale yellow oil. MS m/z: 291.5 (M+H). Calc""d for C16H26N4O-290.40.
15] 1-(6-Aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid as a white solid. MS m/z: 220.3 (Mxe2x88x92H). Calc""d for C11H15N3O2-221.26.
16] 2-Amino-6-[(3-methylpiperidyl)methyl]pyridine as a pale yellow solid. MS m/z: 206.5 (M+H). Calc""d for C12H19N3xe2x80x94205.30.
17] 1-(6-Aminopyridin-2-ylmethyl)-piperidine-3-carboxylic acid as a pale yellow oil. MS m/z: 235.0 (M+H). Calc""d for C12H17N3O2xe2x80x94235.28.
Preparation P: 4-(6-Aminopyridin-2-yloxy)-benzonitrile
To a stirred solution of 4-cyanophenol (1.7 g, 14.3 mmol) in 45 mL dry DMF was added NaH (0.71 g, 17.7 mmol). After stirring at RT for 15 min, 2,6-dibromopyridine (3.2 g, 13.4 mmol) was added and the mixture was heated at 95xc2x0 C. for 24 h. After cooling to RT, 100 mL of H2O was added and the mixture was extracted with EtOAc (2xc3x97100 mL). The combined organic layers were washed with 40 mL brine, dried over MgSO4 and concentrated in vacuo. The crude intermediate was dissolved in 20 mL IpOH, transferred to a Teflon lined pressure vessel and 20 mL of conc. NH4OH was added. Powdered Cu (1 g) was added and the vessel was sealed and heated at 140xc2x0 C. for 24 h. After cooling to RT, the Cu was removed by filtration and the filtrate was diluted with 75 mL of H2O and extracted with EtOAc (2xc3x9775 mL). The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The compound was purified by chromatography on silica gel using 10:1 CHCl3/(xcx9c2M NH3/MeOH) as eluent to afford the title compound as a dark oil. MS m/z: 212.2 (M+H).
The following compounds were prepared from 2,6-dibromopyridine in a manner similar to that described in General Preparation P:
1] 6-Phenoxy-pyridin-2-ylamine: MS m/z: 187.2 (M+H). Calc""d for C11H10N2O: 186.08.
2] 6-(4-Methylphenyloxy)pyridin-2-ylamine: MS m/z: 201.3 (M+H). Calc""d for C12H12N2O: 200.09.
3] 6-(2,4-Dimethylphenyloxy)pyridin-2-ylamine: MS m/z: 215.3 (M+H). Calc""d for C13H14N2O: 214.11.
4] 6-[4-(1-Imidazolyl)phenyloxy]pyridin-2-ylamine: MS m/z: 253.3 (M+H). Calc""d for C14H12N4O: 252.10.
5] 6-[4-[1,3]Dioxolan-2-yl-phenoxy)pyridin-2-ylamine: MS m/z: 259.3 (M+H). Calc""d for C14H14N2O3: 258.10.
6] 6-(4-Fluorophenyloxy)pyridin-2-ylamine: MS m/z: 205.2 (M+H). Calc""d for C11H9FN2O: 204.07.
7] 6-(4-Difluorophenyloxy)pyridin-2-ylamine: MS m/z: 223.2 (M+H). Calc""d for C11H8F2N2O: 222.06.
8] tert-Butyl {2-[4-(6-aminopyridin-2-yloxy)phenyl]ethyl}carbamate: MS m/z: 330.4 (M+H). Calc""d for C18H23N3O3: 329.17.
9] 6-(2-Dimethylaminoethoxy)pyridin-2-ylamine: MS m/z: 182.2 (M+H). Calc""d for C9H15N3O: 181.12.
10] 6-[(1-Methylpyrrolidin-2-yl)methoxy]pyridin-2-ylamine: MS m/z: 208.3 (M+H). Calc""d for C11H17N3O: 207.14.
11] 6-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)pyridin-2-ylamine: MS m/z: 220.3 (M+H). Calc""d for C12H17N3O: 219.14.
12] tert-Butyl 3-[(6-aminopyridin-2-yl)oxymethyl]-azetidine-1-carboxylate: MS m/z: 280 (M+H). Calc""d for C14H21N3O3: 279.16.
13] tert-Butyl 4-[2-(6-Aminopyridin-2-yloxy)ethyl]-piperidine-1-carboxylate: MS m/z: 322 (M+H). Calc""d for C17H27N3O3: 321.21.
Preparation Q: 2-Bromo-6-[Nxe2x80x2-tert-butoxycarbonyl-Nxe2x80x2-2-(1-hydroxy-4-methyl)pentylamino]methylpyridine
To 2-bromo-6-[2-N-(1-hydroxy-4-methyl)-pentylamino]methylpyridine (550 mg, 1.91 mmol) in dry CH2Cl2 (10 mL) was added (Boc)2O (460 mg, 2.106 mmol). The resulting mixture was stirred under N2 at RT for 15 h. The solvent was removed and the residue was extracted with CHCl3. The organic layer was wash with H2O, brine, and dried over MgSO4 and removed to give a yellow liquid. MS m/z:387.6(M+H). Calc""d for C17H27BrN2O3: 387.32.
The following BOC protected compounds were prepared from the corresponding amines (prepared by Preparation N) in a manner similar to that described in General Preparation Q:
1] 2-Bromo-6-[(N-tert-butoxycarbonyl-N-(3-hydroxypropyl)amino]methylpyridine was prepared from 2-bromo-6-[(3-hydroxypropyl)-amino]-methylpyridine (300 mg, 1.22 mmol) [purified by chromatography on silica gel (hexane/acetone, 80/20]) as a colorless oil. MS m/z: 345.1 (M+H).
Calc""d for C14H21BrN2O3xe2x80x94345.23.
Preparation R: 2,2-Dimethyl-N-[6-(2-methylimidazol-1-ylmethyl)pyridin-2-yl]propionamide
A solution of 2-methylimidazole (68 mg, 0.83 mmol) in dry THF (8 mL) was treated under N2 with NaH (33 mg, 0.83 mmol, 60% in mineral oil) at 0xc2x0 C. After the addition, the mixture was warmed to RT and stirred for 0.5 h. It was then treated dropwise with a solution of N-pivaloyl-2-amino-6-bromomethylpyridine (150 mg, 0.55 mmol; M. V. Papadopoulou, et al., J. Heterocyclic Chem., 1995, 32, 675-681) in dry THF (10 mL) over period of 15 min. After the addition, it was stirred for 1 h. The resulting mixture was quenched with saturated NH4Cl (3 mL). Solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo to yield the title compound as light brownish solid. MS m/z: 272.2 (M+H). Calc""d. for C16H21N3Oxe2x80x94271.37.
The following amines were prepared from the corresponding bromomethylpyridine in a manner similar to that described in Preparation R:
1] 2,2-Dimethyl-N-[6-(4-(N,N-dimethylamino-methyl)phenyloxymethyl)pyridin-2-yl]propionamide. MS m/z: 342 (M+H).
Preparation S: N-(6-Azidomethylpyridin-2-yl)-2,2-dimethylpropionamide
N-Pivaloyl-2-amino-6-bromomethylpyridine (1.1 g, 4.05 mmol; M. V. Papadopoulou, et al., J. Heterocyclic Chem., 1995, 32, 675-681) was dissolved in dry THF (15 mL). NaN3 (530 mg, 8.1 mmol) and dry DMF (5 mL) was added and the resulting mixture was heated to reflux under N2 for 2 h. After cooling to RT, solvent was removed and the residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a pale yellow solid. MS m/z: 234.1 (M+H). Calc""d. for C11H15N5Oxe2x80x94233.28.
Preparation T: 6-Azidomethyl-pyridin-2-ylamine
2-(Nxe2x80x2-Pivaloyl)amino-6-azidomethylpyridine (680 mg, 2.91 mmol) was dissolved in MeOH (20 mL) and KOH was added (3.4 g, 60.6 mmol). The resulting mixture was heated to reflux under N2 for 2 h. After cooling to RT, pH was adjusted to 7 followed by removing the solvent. The residue was partitioned between H2O and CHCl3 and the aqueous layer was extracted more with CHCl3. The combined organic layers was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo to yield the title compound as brown solid. MS m/z: 150.3 (M+H). Calc""d. for C6H7N5: 149.15.
The following amines were prepared from the corresponding bromo compounds (prepared by Preparations R-S, and AA) in a manner similar to that described in Preparation T:
1] 3-(2-Methylimidazol-1-ylmethyl)phenylamine. MS m/z: 189.3 (M+H). Calc""d. for C10H12N4-188.23.
2] 2-Amino-6-[4-(dimethylamino)methyl]phenoxymethyl-pyridine. MS m/z: 258 (M+H).
3] 2-Amino-6-[1-(N-tert-butoxycarbonyl) amino]-ethoxymethyl-pyridine. MS m/z: 268 (M+H).
4] 2-Amino-6-[4-(methylphenyl)oxymethyl]pyridine. MS m/z: 215 (M+H).
5] 2-Amino-6-[1-(N-tert-butoxycarbonyl)amino]-ethoxymethyl-pyridine. MS m/z: 267 (M+H)
6] 2-Amino-5-[1-morpholinylmethyl]pyridine. MS m/z: 194 (M+H).
7] 5-Methoxymethyl-pyridin-2-ylamine.
Preparation U: Methyl 1-(6-aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylate
Concentrated H2SO4 (1.0 mL) was added to a solution of 1-(6-aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid (620 mg, 2.80 mmol) in MeOH (15 mL) and the resulting mixture was heated at 80xc2x0 C. for 10 h. After cooling to RT, the mixture was quenched with saturated 2 M Na2CO3 solution and concentrated in vacuo. CHCl3 (15 mL) was added and the solution washed with 1.0 N NaOH solution (15 mL). The organics were collected and the aqueous layer was extracted with CHCl3/IpOH (3/1, 3xc3x9710 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The crude compound was purified by chromatography on silica gel (CH2Cl2/MeOH, 95/5) to give a pale yellow oil. MS m/z: 236.1 (M+H). Calc""d for C12H17N3O2xe2x80x94235.28.
Preparation V: 3-Methyl-2-(phthalimidyl)pyridine
2-Amino-3-picoline (1.00 mL, 8.62 mmol) was dissolved in DMF (30 mL) at 230C, and treated with solid carboethoxy-phthalimide (1.89 g, 8.64 mmol), followed by TEA (1.44 mL, 10.3 mmol). The resulting solution was stirred at 230C for 15 h. After 15 h, the mixture was diluted with EtOAc (50 mL), and washed with saturated NaCl (1xc3x9750 mL), H2O (1xc3x9750 mL), dried (MgSO4), and concentrated in vacuo to a yellow solid. Purification over silica gel (0 to 50% EtOAc/Hexanes) provided the title compound as a white solid.
Preparation W: 3-(Dibromomethyl)-2-(phthalimidyl)pyridine
3-Methyl-2-(phthalimidyl)pyridine (360 mg, 1.51 mmol) was dissolved in CCl4 (5 mL), and treated with NBS (267 mg, 1.50 mmol), followed by AIBN (46.9 mg, 0.29 mmol). The resulting suspension was warmed to reflux for 2 h, treated again with AIBN (55.4 mg, 0.34 mmol), and heated at reflux an additional 12 h. After 12 h, AIBN was again added (96.7 mg, 0.59 mmol) and reflux was continued. After 2 h, more AIBN was added (59.6 mg, 0.36 mmol), and reflux continued. After 2 h, additional NBS was added (253 mg, 1.42 mmol) and the mixture was treated with additional AIBN (49.6 mg, 0.30 mmol), and heated at reflux an additional 12 h. The mixture was cooled to RT, diluted with EtOAc (50 mL), washed with saturated NaCl (1xc3x9750 mL), then dried (MgSO4) and concentrated in vacuo. The resulting white solid was purified over silica gel (0 to 40% EtOAc/Hexanes) to provide the title compound. MS m/z: 397 (M+H).
Preparation X: 2-(phthalimidyl)-3-(1-piperidinylmethyl)-pyridine
3-(Dibromomethyl)-2-(phthalimidyl)pyridine (185 mg, 0.47 mmol) was dissolved in CH2Cl2 (2 mL) and treated with piperidine (0.460 mL, 4.66 mmol), and glacial AcOH (0.160 mL, 2.80 mmol) in a dropwise fashion. The resulting yellow solution was stirred at 23xc2x0 C. for 2 h, then treated with solid NaBH(OAc)3 (393 mg, 1.86 mmol) in one portion, and stirring was continued for 14 h. After stirring 14 h at 23xc2x0 C., the mixture was treated with 2M K2CO3 (6 mL), and stirred for 1 h. After 1 h, the mixture was diluted with EtOAc (50 mL) and washed with H2O (1xc3x9750 mL), and saturated NaCl (1xc3x9750 mL). The organic phase was then dried (MgSO4) and concentrated in vacuo to provide the title compound as a yellow residue. The crude material was used in subsequent transformations without further purification. MS m/z: 323 (M+H).
Preparation Y: 2-Amino-3-(1-piperidinylmethyl)-pyridine
2-(Phthalimidyl)-3-(1-piperidinylmethyl)-pyridine (196 mg, 0.609 mmol) was dissolved in EtOH (95%, 2 mL) at 23xc2x0 C., and treated with hydrazine monohydrate (0.0320 mL, 0.670 mmol) in a dropwise fashion. The resulting mixture was warmed to reflux and stirred for 3 h at reflux. The solution was treated with additional hydrazine monohydrate (0.150 mL, 3.050 mmol), and reflux continued. After 14 h at reflux, the mixture was cooled to RT, and concentrated using a rotary evaporator to a white paste. The resulting white paste was dissolved in CHCl3:IpOH (3:1, 75 mL), and washed with saturated NaHCO3 (3xc3x9750 mL), and H2O (1xc3x9750 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound as a white solid. MS m/z: 192 (M+H).
Preparation Z: N-Pivaloyl 2-amino-5-(bromomethyl) pyridine
N-Pivaloyl-2-amino-5-methylpyridine (5.12 g, 26.6 mmol) was dissolved in CCl4 (75 mL) at 23xc2x0 C., and treated with NBS (9.69 g, 54.4 mmol), followed by AIBN (937 mg, 5.71 mmol) with stirring. The resulting orange, biphasic suspension was then warmed to reflux for 4 h. After 4 h at reflux, the rust-colored mixture was cooled to RT, filtered through a Celite(copyright) pad, and concentrated in vacuo to a red residue. Purification over silica gel (gradient, 0 to 25% EtOAc/hexanes) provided the title compound as a light yellow solid. MS m/z: 272 (M+H).
Preparation AA: N-Pivaloyl-2-amino-5-[2-(N-tert-butoxycarbonyl)amino]ethoxymethylpyridine
N-Pivaloyl-2-amino-5-bromomethylpyridine (484 mg, 1.78 mmol) was dissolved in THF (6 mL) at 23xc2x0 C., and treated with 2-(N-tert-butoxycarbonyl)aminoethanol (0.551 mL, 3.56 mmol), followed by NaH (60% suspension in mineral oil, 221 mg, 5.52 mmol) with stirring. The resulting mixture was stirred at 23xc2x0 C. for 14 h, then treated with additional NaH (75.6 mg, 1.89 mmol) as well as DMSO (1 mL), and stirred an additional 5 h at 230C. After 5 h at 230C, the solution was warmed to 55xc2x0 C. for 3 h, then cooled to RT. The mixture was treated with saturated NaHCO3 (10 mL), diluted with EtOAc (50 mL), and washed with saturated NaHCO3 (2xc3x9750 mL). The mixture was dried over MgSO4 and purified over silica gel to provide the title compound as a pale yellow oil. MS m/z: 352 (M+H).
The following amines were prepared from the corresponding bromomethylpyridine in a manner similar to that described in General Preparation AA:
1] 2,2-Dimethyl-N-[6-(N-(tert-butoxycarbonyl)-amino-1-ethoxymethyl)pyridin-2-yl]propionamide. MS m/z: 352 (M+H).
2] N-Pivaloyl-2-amino-6-[(4-methylphenyl)-oxymethyl]-pyridine. MS m/z: 299 (M+H).
3] N-Pivaloyl-2-amino-5-[(4-methylphenyl)-oxymethyl]pyridine. MS m/z: 299 (M+H).
Preparation AB: N-Pivaloyl-2-amino-5-[1-morpholinylmethyl]pyridine
N-Pivaloyl-2-amino-5-bromomethylpyridine (478 mg, 1.76 mmol) was dissolved in THF at 23xc2x0 C. with stirring and treated with morpholine (0.770 mL, 8.81 mmol) in a dropwise fashion. The resulting brown mixture was stirred at 23xc2x0 C. for 14 h. After stirring 14 h, the mixture was treated with saturated NaHCO3 (2 mL) and stirred an additional 5 h at 23xc2x0 C. After 5 h, the brown mixture was warmed to 55xc2x0 C. for 3 h, then cooled to RT and diluted with EtOAc (50 mL). The mixture was washed with saturated NaHCO3 (2xc3x9750 mL), dried (MgSO4), and concentrated to a brown residue which was immediately purified over silica gel (0 to 5% MeOH/CHCl3) to provide the title compound as a yellow oil. MS m/z: 278 (M+H).
Preparation AC: 2-(Butyloxycarbonyl)amino-6-methylpyridine
To a 2-L 3-neck Miller flask charged with 2-amino-6-methylpicoline (15 g, 138.7 mmol) and dry THF (1 L) was added di-tert-butyl dicarbonate (33.3 g, 152.6 mmol) then TEA (21.2 mL, 152.6 mmol) via addition funnel at 0xc2x0 C. The reaction mixture was warmed to RT and added DMAP (1.7 g, 13.9 mmol). After 3.5 h, extracted with EtOAc, washed with saturated NH4Cl, H2O (3xc3x97), and brine (3xc3x97), dried (MgSO4) and concentrated in vacuo to afford the crude material as a turbid yellow oil. Trituration with hexane formed a precipitate which was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil.
Preparation AD: 6-Bromomethyl-2-(butyloxycarbonyl)amino-pyridine
To a solution of N-Boc-2-amino-6-picoline (28.7 g, 138 mmol) and CCl4 (500 mL) was added NBS (27.1 g, 151.8 mmol) and AIBN (2.3 g, 13.8 mmol) and heated to reflux. After 2 h, added 0.1 equivalent of AIBN. The reaction mixture was heated at reflux for 20 h, filtered and concentrated in vacuo to give a dark oil. Purified by silica flash chromatography (100% hexane to 5% EtOAc/Hexane) to afford the desired as a yellow oil. MS m/z: 288.0 (M+H)
Preparation AE: 2-(Butyloxycarbonyl)amino-6-cyanomethylpyridine
To a solution of N-Boc-2-amino-6-methylbromidepyridine (12 g, 41.8 mmol) and EtOH (250 mL) was added NaCN (2 g, 41.8 mmol). The reaction mixture was heated to reflux for 2 h then cooled to RT and concentrated in vacuo. Purification by silica flash chromatography (100% Hexane to 20% EtOAc/Hexane) afforded the title compound as a yellow oil. MS m/z: 234.0 (M+H).
Preparation AF: 2-Amino-6-cyanomethylpyridine
To a solution of N-Boc-2-amino-6-methylnitrilepyridine and CH2Cl2 (10 mL) was added TFA (8 mL) and stirred at RT. After 3 h, the mixture was concentrated in vacuo, diluted with EtOAc and saturated NaHCO3 was carefully added. The mixture was washed with saturated NaHCO3 (2xc3x97) and brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid.
Preparation AG: 6-Aminoethyl-2-(butyloxycarbonyl)amino-pyridine
A solution of N-Boc-2-amino-6-methylnitrile-pyridine (1 g, 4.3 mmol) and EtOH (25 mL) was hydrogenated over 20% Pd(OH)2/C at RT and 40 psi. After 18 h, the mixture was filtered through Celite(copyright) and eluted with EtOAc. The filtrate was concentrated in vacuo to afford the title compound as a white foamy solid.
Preparation AH: 2-Amino-6-(phthalimidyl)ethyl-pyridine
To a solution of N-Boc-2-amino-6-ethylaminopyridine (1 g, 4.3 mmol) and CHCl3 (25 mL) was added phthalic anhydride (0.64 g, 4.3 mmol). Heated to 70xc2x0 C. for 15 h then at RT for 5 days. The mixture was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give crude N-Boc-2-amino-6-ethylphthalamidylpyridine, which was used without further purification. To a solution of crude N-Boc-2-amino-6-ethylphthalamidylpyridine (1.6 g, 4.3 mmol) and CH2Cl2 (10 mL) was added 10 mL of TFA and the mixture was stirred at RT. After 30 min, the mixture was concentrated in vacuo. The residue was diluted with 90% MeOH/CH2Cl2 and treated with solid NaHCO3, stirred for 15 min then filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid. MS m/z: 268.2 (M+H).
Preparation AI: 2-[(6-Bromopyridin-2-yl)methylamino]-propan-1-ol
To a stirred solution of the (6-bromo-2-pyridyl)-formaldehyde (0.52 g, 2.8 mmol) in toluene (14 mL) was added DL-2-amino-1-propanol (0.67 mL). The resulting mixture was heated to reflux with a Dean-Stark trap for 3 h under N2 until complete formation of the imine was observed. The mixture was brought to RT followed by the addition of a solution of NaBH(OAc)3 (2.0 g, 9.8 mmol) in ACOH (6 mL). The resulting mixture was stirred at RT and under N2 for 56 h. The mixture was neutralized (pH 7.0) with a saturated solution of NaHCO3 (aq) and extracted with CH2Cl2 (3xc3x9750 mL). The aqueous layer was concentrated by rotary evaporation and the residue obtained was extracted with CH2Cl2 (3xc3x9750 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a pale yellow oil. EI-MS m/z 245 (M+H).
Preparation AJ: (tert-Butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-(2-hydroxy-isopropyl)carboxamide
To a stirred solution of 2-[(6-bromo-2-pyridyl)-methyl]aminopropan-1-ol (0.55 g, 2.2 mmol) in dry CH2Cl2 (11 mL) was added Boc2O (0.51 g, 2.42 mmol). The resulting mixture was stirred at RT and under N2 for 15 h. The mixture was concentrated by rotary evaporation and purified on silica gel (2:1 hexanes/EtOAc, 5:95 MeOH/CH2Cl2 and, 10:90 MeOH/CH2Cl2) as eluent to afford the title compound as an off-white oil. EI-MS m/z 345 (M+H).
Preparation AK: (tert-Butoxy-N-[(6-bromo(2-pyridyl))-methyl]-N-(1-methyl-2-oxoethyl)carboxamide
To a dry flask was added oxalyl chloride (72 xcexcL) followed by the addition of dry CH2Cl2 (2 mL). The resulting colorless solution was brought to xe2x88x9263xc2x0 C. (dry ice/CHCl3) and a solution of DMSO (80 xcexcL) in 0.5 mL dry CH2Cl2 was slowly added dropwise. A solution of (tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-(2-hydroxy-isopropyl)carboxamide (0.19 g, 0.55 mmol) in dry CH2Cl2 (2 mL), was added slowly drop wise. The resulting mixture was kept at xe2x88x9263xc2x0 C. and stirred for 30 min, followed by the slow addition of a solution of TEA (0.31 mL) in dry CH2Cl2 (1 mL). The mixture was stirred at xe2x88x9263xc2x0 C. until all the starting material was consumed (checked by MS). The mixture was brought to xe2x88x9220xc2x0 C., quenched with a saturated solution of NH4Cl (aq) and diluted with EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc (3xc3x9720 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a pale yellow semi-solid. EI-MS m/z 343 (M+H).
Preparation AL: N-[2-(diethylamino)-isopropyl](tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-carboxamide
To a stirred solution of (tert-butoxy-N-[(6-bromo(2-pyridyl))methyl]-N-(1-methyl-2-oxoethyl)-carboxamide (0.15 g, 0.44 mmol) in toluene (3 mL) was added DEA (0.2 mL). The resulting mixture was heated to reflux in a Dean-Stark trap under N2 for 3 h. The mixture was brought to RT followed by the addition of a solution of NaBH(OAc)3 (0.33 g, 1.54 mmol) in AcOH (6 mL). The yellow-solution was stirred at RT and under N2 for 15 h. The mixture was diluted with EtOAc (20 mL) and washed with a saturated solution of NaHCO3 (aq) (50 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated by rotary evaporator to afford the title compound as a brown/yellow oil. EI-MS m/z 400 (M+H).
Preparation AM: N-[2-(diethylamino)isopropyl](tert-butoxy)-N-[(6-amino(2-pyridyl))methyl]-carboxamide
To a stirred solution of N-[2-(diethylamino)-isopropyl](tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-carboxamide (80 mg 0.2 mmol) in IpOH (4 mL) in a sealed tube, was added NH4OH (28-30%, 6 mL) followed by an excess of Cu. The resulting solution was heated under pressure at 90xc2x0 C. for 24 h. The mixture was brought to RT, diluted with H2O (20 mL) and extracted with CHCl3 (3xc3x9720 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a pale-yellow oil. EI-MS m/z 337 (M+H).
Preparation AN: Methyl 2-[(6-bromo-2-pyridylmethyl)amino]-3-methyl-butyrate
To a stirred solution of L-valine methyl ester hydrochloride (0.54 g, 3.24 mmol) in dry toluene (15 mL) at 80xc2x0 C. was added DIEA (2.0 mL 11 mmol) followed by (6-bromo-2-pyridyl)formaldehyde (0.50 g, 2.70 mmol). The resulting mixture was heated at 80xc2x0 C. for 3 h. The reaction was brought to RT and a solution of NaBH(OAc)3 (1.4 g, 6.75 mmol) in glacial AcOH (4 mL) was added. The resulting mixture was stirred for 15 h and concentrated by rotary evaporation. The resulting yellow oil was dissolved in CH2Cl2 (100 mL), washed with a saturated solution of NaHCO3 (aq) (50 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated by rotary evaporation and purified by flash chromatography (2:1 hexanes/EtOAc) to afford the title compound as a pale-yellow oil. EI-MS m/z 301 (M+H).
Preparation AO: 2-[(6-Bromo-2-pyridylmethyl)amino]-3-methyl-butanol
To a stirred solution of (tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[2-oxomethoxide-1-(methylethyl)-ethyl]carboxamide (0.47 g, 1.57 mmol) in dry toluene (25 mL) at xe2x88x9278xc2x0 C. was added dropwise DIBAL-H (1.0 M solution in hexane, 4.7 mL). The resulting brown-solution was stirred at xe2x88x9278xc2x0 C. for 3 h, brought to RT and stirred until starting material was consumed. The organic layer was separated, dried over Na2SO4, filtered, concentrated by rotary evaporation and purified on silica gel (10:90 MeOH/CH2Cl2) to afford the title compound as a yellow oil. EI-MS m/z 273 (M+H).
Preparation AP: Tert Butyl(6-bromopyridin-2-ylmethyl)-(1-hydroxymethyl-2-methyl-propyl)-carbamate
To a stirred solution of 2-[(6-bromo-2-pyridylmethyl)amino]-3-methyl-butanol (0.30 g, 1.10 mmol) in CH2Cl2 (5 mL) was added Boc2O (0.26 g, 1.21 mmol). The resulting solution was stirred for 15 h, concentrated by rotary evaporation and purified on silica gel (5:95 MeOH/CH2Cl2 and 10:90 MeOH/CH2Cl2) to afford the title compound as a pale yellow solid. EI-MS m/z 373 (M+H).
Preparation AQ: Tert Butyl (6-bromopyridin-2-ylmethyl)-(1-formyl-2-methyl-propyl)carbamate
To a flame-dried flask was added oxalyl chloride (70 xcexcL) followed by the addition of dry CH2Cl2 (2 mL). The resulting colorless solution was brought to xe2x88x9263xc2x0 C. (dry ice/CHCl3) and a solution of DMSO (70 xcexcL) in 0.5 mL dry CH2Cl2 was slowly added drop wise. The (tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[2-hydroxy-1-(methylethyl)ethyl]carboxamide (0.19 g, 0.51 mmol), previously dissolved in dry CH2Cl2 (2 mL), was added slowly dropwise. The resulting mixture was kept at xe2x88x9263xc2x0 C. and stirred for 30 min followed by the slowly addition of a solution of TEA (0.3 mL) in dry CH2Cl2 (1 mL). The mixture was stirred at xe2x88x9263xc2x0 C. until all the starting material was consumed (checked by MS) (1.5 h). The mixture was brought to xe2x88x9220xc2x0 C., quenched with a saturated solution of NH4Cl (15 mL) and diluted with EtOAc (35 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3xc3x9730 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation without further purification to afford the title compound as a yellow-semi solid. EI-MS m/z 371 (M+H).
Preparation AR: tert-Butyl(6-bromopyridin-2-ylmethyl)-(1-diethylaminomethyl-2-methyl-propyl)carbamate
To a stirred solution of (tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[1-(methylethyl)-2-oxoethyl]carboxamide (0.17 g, 0.46 mmol) in toluene (5 mL) was added DEA (0.14 mL). The resulting mixture was heated to reflux in a Dean-Stark trap under N2 for 3 h. The mixture was brought to RT followed by the addition of a solution of NaBH(OAc)3 (0.34 g, 1.61 mmol) in glacial AcOH (6 mL). The yellow-solution was stirred at RT and under N2 for 15 h. The mixture was diluted with EtOAc (20 mL) and washed with a saturated solution of NaHCO3 (aq) (15 mL). The aqueous layer was separated and concentrated under reduced pressure. The solid obtained was extracted with CH2Cl2. The extracts were combined, dried over MgSO4, filtered and, concentrated by rotary evaporation to afford the title compound as a pale yellow oil. EI-MS m/z 428 (M+H).
Preparation AS: tert-Butyl(6-aminopyridin-2-ylmethyl)-(1-diethylaminomethyl-2-methyl-propyl)carbamate
To a stirred solution of N-{1-[(diethylamino)-methyl]-2-methylpropyl}(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]carboxamide (5 mg, 0.012 mmol) in IpOH (5 mL) in a sealed tube, was added NH4OH (28-30% 6 mL) followed by excess Cu. The resulting solution was heated under pressure at 90xc2x0 C. for 24 h. The mixture was brought to RT, diluted with H2O (10 mL) and extracted with CHCl3 (3xc3x9720 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a green oil. No purification was required. EI-MS m/z 365 (M+H).
Preparation AT: 2-Bromo-6-(piperidin-1-ylmethyl)pyridine
To a stirred solution of 6-bromo-2-pyridine carboxaldehyde (5.05 g, 27 mmol) in anhydrous CH2Cl2 (200 mL) at RT, under N2, piperidine (2.95 mL, 29 mmol) was added, followed by NaBH(OAc)3 (11.51 g, 54 mmol) and AcOH (6.2 mL, 108 mmol) 30 min later. After 20 h, a 2M solution of Na2CO3(aq) (20 mL) was added. The mixture was vigorously stirred for an additional 30 min, washed successively with a saturated solution of NaHCO3(aq) until the pH of the aqueous layer reached 7 (2xc3x97100 mL), H2O (100 mL) and brine (100 mL) The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil. This was used crude in the next step. MS m/z: 255 (M+H), 257 (M+3).
Preparation AU: 2-Amino-6-(piperidin-1-ylmethyl)pyridine
To a solution of 2-bromo-6-(piperidylmethyl)pyridine (5.21 g, 20 mmol) in IpOH (30 mL) in a sealed tube at RT, a catalytic amount of Cu (100 mg) and 28-30% NH4OH (35 mL) were added. The stirred suspension was heated to 95xc2x0 C. for 40 h. After cooling to RT, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4xc3x9780 mL). The organic layers were combined, then washed with H2O (50 mL) followed by brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a dark yellow oil. This was used as crude. MS m/z: 193 (M+H)+.
Preparation AV: Ethyl 2-(4-aminosulfonylphenyl) thiazole-4-carboxylate
In an oven-dried, 100-mL, round-bottomed flask were placed 4-cyanobenzenesulphonamide (4.1 g, 22.50 mmol), TEA (5 mL) in pyridine (40 mL). H2S was bubbled through this mixture for 1 h at RT. The reaction was diluted with EtOAc (125 mL) and H2O (50 mL). The phases were separated, and the organic layer was washed with H2O (4xc3x9725 mL) and brine (15 mL), dried over MgSO4, and concentrated in vacuo to afford the crude thiobenzamide as an oily solid; MS m/z: 217 (M+H). In an oven-dried, 100-mL, round-bottomed flask were placed the crude thiobenzamide, ethyl bromopyruvate (3.0 mL, 23.66 mmol) in EtOH (40 mL). The reaction was heated to 75xc2x0 C. for 12 h, then cooled to RT. The mixture was concentrated in vacuo to give the crude sulfonamide as a yellow solid which was filtered, washed with H2O (1xc3x9710 mL) and Et2O (4xc3x9710 mL) to afford the title compound as a yellow solid. MS m/z: 313 (M+H).
Preparation AW: 2-(4-Aminosulfonylphenyl)thiazole-4-carboxylic Acid
In an oven-dried, 100-mL, round-bottomed flask was placed ethyl 2-(4-aminosulfonylphenyl)thiazole-4-carboxylate (1300 mg, 4.2 mmol), LiOH monohydrate (350 mg, 8.3 mmol) in MeOH (40 mL) and H2O (4 mL). The solution was heated to 75xc2x0 C. for 3 h, cooled to RT, and concentrated. The resulted yellow solid was dissolved in H2O (10 mL), extracted with EtOAc (1xc3x9715 mL). The aqueous layer was acidified with 2N aqueous HCl (4.15 mL). The precipitate was filtered, and washed with H2O (10 mL) to afford the title compound as a light-yellow solid. MS m/z: 285 (M+H).
Preparation AX: 2-(4-(4-morpholinyl)sulfonylphenyl)-thiazole-4-carboxylic Acid
In a manner similar to that described for the preparation of 2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid, 460 mg of 4-(morpholinosulfonyl)-benzonitrile was treated with H2S, ethyl bromopyruvate, and LIOH successively to give the title compound. MS m/z: 355 (M+H).
Preparation AY: 2-(4-Boc-aminophenyl)-thiazole-4-carboxylic acid
In a manner similar to that described for the preparation of 2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid, 4-[(1,1-dimethylethoxy)carbonyl]-aminobenzonitrile was treated with H2S, ethyl bromopyruvate, and LiOH successively to give the title compound. MS m/z: 321 (M+H).
Preparation AZ: Ethyl 2-(phenoxy)thiazole-4-carboxylate
A mixture of the bromothiazole (1.03 g, 4.36 mmol) and phenol (10.0 g, 106 mmol) was stirred at 180xc2x0 C. for 1 h, cooled to RT, diluted with 100 mL of EtOAc, washed with 1N NaOH (40xc3x973), H2O, and brine, then dried over MgSO4, and concentrated in vacuo to yield a light yellow residue. Purification over silica gel (gradient, 5% to 10% EtOAc/hexanes) provided the title compound. MS m/z: 250 (M+H)++.
Preparation BA: 2-(Phenoxy)thiazol-4-ylcarbonylazide
TEA (0.17 mL, 1.20 mmol) was added to a solution of the thiazole carboxylic acid (0.13 g, 0.59 mmol) in 10 mL of THF at 0xc2x0 C. The mixture was stirred at 0xc2x0 C. for 20 min whereupon ethyl chloroformate (0.065 mL, 0.65 mmol) was added. After the mixture was stirred for 30 min, a solution of NaN3 (0.043 g, 0.65 mmol) in 3 mL of H2O was added, the reaction was stirred for 30 min, then warmed to RT, diluted with 25 mL of H2O, and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and removal of the solvents in vacuo yielded the title compound as a light brownish solid. MS m/z: 247 (M+H).
Preparation BB: 6-Chloro-thionicotinamide
To a solution of the 4-chloronicotinamide (5 g, 31.9 mmol) and dry THF (200 mL) was added P2S5 (15.6 g, 35.1 mmol) and Na2CO3 (3.7 g, 35.1 mmol). The mixture was heated at reflux for 1.5 h, cooled and filtered off a yellow solid. The filtrate was extracted with EtOAc, washed with H2O and brine; dried (MgSO4) then concentrated in vacuo to give the title compound as a yellow solid. MS m/z: 173.0 (M+H).
Preparation BC: Ethyl 2-(6-chloro-3-pyridyl)thiazole-4-carboxylate
To a mixture of the 4-chloro-thionicotinamide (5.5 g, 31.9 mmol) and EtOH (300 mL) was added bromo-ethyl-pyruvate (4.4 mL, 35.1 mmol). The mixture was heated at reflux for 15 h, cooled and concentrated in vacuo to afford a yellow solid/orange oil. The oil was diluted with EtOAc and filtered off yellow solid. The filtrate was filtered through Celite(copyright) and concentrated in vacuo to give a dark yellow oil. The oil was diluted with 2% MeOH/CH2Cl2 and filtered through a pad of silica gel (150 mL). Elution with 2% MeOH/CH2Cl2 (500 mL), followed by concentration in vacuo afforded the title compound as a yellow crystalline solid. MS m/z: 269.1 (M+H).
Preparation BD: 2-(6-Methoxy-3-pyridyl)thiazole-4-carboxylic Acid
To a solution of the ethyl 2-(6-chloro-3-pyridyl)thiazole-4-carboxylate (0.61 g, 2.3 mmol) and MeOH (50 mL) was added solid NaOMe (135 mg, 2.5 mmol) and stirred at RT. After 3 h the ethyl ester transesterified to the methyl ester. NaOMe (1 eq, 135 mg) was added and the mixture was heated to reflux. After 15 h, the ester hydrolyzed to the 2-(6-chloro-3-pyridyl)thiazole carboxylic acid. NaOMe (2 eq) was added and the reaction was heated at reflux for 18 h. The mixture was acidified to pH 5 with concentrated HCl, extracted with EtOAc, washed with H2O and brine; dried (MgSO4) and concentrated in vacuo to give the desired carboxylic acid as a yellow solid. MS m/z: 237.1 (M+H).
Preparation BE: 2-(2-Chloropyridin-4-yl)thiazole-4-carbonyl Azide
A mixture of 3-(3-chloro-4-pyridyl)-4-thiazole carboxylic acid (0.6 g, 2.5 mmol) and dry THF (20 mL) was cooled to 0xc2x0 C. with stirring. TEA (0.7 mL, 5.0 mmol) was added and the reaction mixture was stirred for 20 min. Ethyl chloroformate (0.24 mL, 2.5 mmol) was added and the solution was stirred for 30 min. A solution of NaN3 (174 mg, 2.7 mmol) in 3 mL of H2O was added and the reaction mixture was warmed to RT. After 30 min, 10 mL of H2O was added and the mixture was extracted with EtOAc (3xc3x97), dried (MgSO4) and concentrated in vacuo to give the title compound as a pink solid. MS m/z: 266.0 (M+H)+.
Preparation BF: Ethyl 2-(3-methoxyphenyl)-thiazole-4-carboxylate
A suspension of 3-methoxyphenyl boronic acid (0.25 g, 1.65 mmol), ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl2(dppf)2 (0.11 g) and 2M Na2CO3 (aq) (2 mL) in DME (10 mL) was heated to reflux for 20 h. The mixture was cooled to RT, filtered, concentrated by rotary evaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1 hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MS m/z 264 (M+H).
Preparation BG: 2-(3-Methoxyphenyl)thiazole-4-carboxylic Acid
To a stirred solution of the ethyl 2-(3-methoxy-phenyl)thiazole-4-carboxylate (0.23 g, 0.87 mmol) in EtOH (10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heated to reflux until the starting material was consumed (2 h). The mixture was cooled to RT, acidified with 1N HCl (aq) and concentrated by rotary evaporation. The residue was extracted with CH2Cl2 (3xc3x9715 mL). The extracts were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as an off-white solid. EI-MS m/z 236 (M+H).
Preparation BH: Ethyl 2-(2-methoxyphenyl)-thiazole-4-carboxylate
A suspension of 2-methoxyphenyl boronic acid (0.25 g, 1.65 mmol), ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl12(dppf)2 (0.11 g, 0.14 mmol) and 2M Na2CO3(aq) (2 mL) in DME (10 mL) was heated at reflux for 20 h, cooled to RT, filtered, concentrated by rotary evaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1 hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MS m/z 264 (M+H).
Preparation BI: 2-(2-Methoxyphenyl)thiazole-4-carboxylic Acid
To a stirred solution of ethyl 2-(2-methoxy-phenyl)thiazole-4-carboxylate (0.27 g, 1.03 mmol) in EtOH (10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled to RT, acidified with 1N HCl (aq) and concentrated by rotary evaporation. The residue was extracted with CH2Cl2 (3xc3x975 mL). The extracts were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as an off-white solid. EI-MS m/z 236 (M+H).
Preparation BJ: 2-[(4-Methoxyphenoxy)methyl]thiazole-4-carboxylic Acid
To a stirred solution of ethyl 2-(4-methoxyphenoxy)methyl]thiazole4-carboxylate (0.10 g, 0.34 mmol) in EtOH (5 mL) was added 1N NaOH (2.0 mL) and was heated to reflux until the starting material was consumed (2 h). The mixture was brought to RT, acidified with 1N HCl (pH 4.0) and concentrated by rotary evaporation. The residue obtained was partitioned between EtOAc (50 mL) and H2O (30 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a white solid. EI-MS m/z 266 (M+H).
Preparation BK: 2-Amino-thiazole-4-carboxylic Acid Ethyl Ester Hydrobromide
To a stirred suspension of thiourea (24.26 g, 0.319 mol) in 200 proof EtOH (350 mL) at RT, under N2, ethyl bromopyruvate (62.16 g, 0.319 mol) was added dropwise. Upon completion the yellow solution was heated to 45xc2x0 C. for 15 h, then placed in a fridge overnight. The precipitate was filtered off and washed with cold EtOH (3xc3x97100 mL) to yield the title compound as a pale yellow amorphous solid. MS m/z: 173.1 (M+H), 195.1 (M+Na). Calc""d. for C6H9BrN2O2S-253.12.
Preparation BL: 2-Bromothiazole-4-carboxylic Acid
To a well stirred suspension of ethyl 2-aminothiazole-4-carboxylate hydrobromide (29.99 g, 0.17 mol) in 16% HBr(aq) (400 mL) at 0xc2x0 C., a solution of NaNO2 (12.49 g, 0.18 mol) in H2O (22 mL) was added dropwise. The mixture was maintained at 0xc2x0 C. for an additional 35 min then CuBr (28.23 g, 0.20 mol) and an additional volume of 16% HBr(aq) (150 mL) were added. The ice bath was removed and the suspension heated to 70xc2x0 C. for 1 hr. The mixture was filtered hot. The filtrate was saturated with NaCl then extracted with EtOAc (2xc3x97400 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude brown oil/solid residue was used directly in the next step. A solution of the brown residue in EtOH (100 mL) and 1M NaOH (aq) (367 mL, 0.36 mol) was stirred and heated at reflux for 1 h. The reaction mixture was filtered then extracted with EtOAc (100 mL). The aqueous layer was separated and concentrated under reduced pressure to remove the remaining EtOH. The aqueous solution was acidified to pH 1 with 2N HCl(aq). The solid was filtered off and air dried to yield the title compound as a beige amorphous solid. MS m/z: 208 (M+H) 210 (M+3).
Preparation BM: Ethyl 2-(2,6-dichloro-4-pyridyl)thiazole-4-carboxylate
2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) was dissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9 mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixture was heated to reflux under N2 for 5 h. After cooling to RT, solvent was removed. The residue was extracted with CHCl3. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to give a brownish solid. This crude was purified by chromatography on silica gel. Elution with hexane:acetone (90:10) gave a title compound as yellow solid. MS m/z: 303 (M+H). Calc""d. for C11H8Cl2N2O2Sxe2x80x94303.16.
Preparation BN: 2-(2,6-Dichloro-4-pyridyl)thiazole-4-carboxylic Acid
2-(2,6-Dichloropyridin-4-yl)-ethylthiazolo-4-carboxylate (500 mg, 1.65 mmol) was dissolved in MeOH (10 mL) followed by adding 1N NaOH (2.5 mL, 2.47 mmol). The resulting mixture was stirred at RT for 4 h. The pH was adjusted to 5 using 1N HCl. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted more with EtOAc. The combined organic layers was dried over MgSO4 and concentrated to give a white solid. MS m/z: 275.1 (M+H). Calc""d. for C9H4Cl2N2O2S-275.11.
Preparation BO: Ethyl 6-[2-(2,2,2-trifluoroethoxy)-3-pyridyl]thiazole-4-carboxylate
6-(2,2,2-Trifluoroethoxy)pyridine-3-thiocarboxamide (800 mg, 3.4 mmol), ethyl bromopyruvate (0.9 mL, 6.8 mmol), and pyridine (0.3 mL, 3.4 mmol) were heated at reflux in dry 1,4-dioxane (20 mL) to yield title compound as pale yellow solid. MS m/z: 333.1 (M+H). Calc""d. for C13H11F3N2O3Sxe2x80x94332.3.
Preparation BP: 6-[2-(2,2,2-trifluoroethoxy)-3-pyridyl]thiazole-4-carboxylic Acid
Ethyl 6-[2-(2,2,2-trifluoroethoxy)-3-pyridyl]thiazole-4-carboxylate (750 mg, 2.25 mmol) and 1N NaOH (3.4 mL, 3.4 mmol) were dissolved in MeOH (10 mL) to afford the title compound as a white solid. MS m/z: 305.1 (M+H). Calc""d. for C11H7F3N2O3S-304.25.
Preparation BQ: 2-(Phenoxy)thiazole-4-carboxylic acid
A mixture of ethyl 2-phenoxythiazole-4-carboxylate (0.17 g, 0.68 mmol) and LIOH monohydrate (0.14 g, 3.40 mmol) in 2 mL of MeOH, 2 mL of H2O, and 2 mL of THF was stirred at RT overnight, the solvents were removed in vacuo and the residue was diluted with water. The aqueous mixture was acidified with 1N HCl (aq) to pH=1-2, then extracted with EtOAc, the combined organic portions were washed with brine, dried over MgSO4, filtered, removal of the solvents in vacuo yielded the title compound as a white solid. EI-MS=222.4 (M+H)+. Calc""d for C10H7NO3S: 221.01.
Preparation BR: 3-(3-Nitrophenyl)pyridine
To a 1-iodo-3-nitrobenzene (1.0 g, 4.01 mmol) in dry DME (20 mL) was added pyridine-3-boronic acid (641 mg, 5.22 mmol), PdCl2 dppf (327 mg, 0.40 mmol), and 2M Na2CO3 (3.0 mL). The resulting mixture was heated to reflux under N2 for 15 h. Solvent was separated from inorganic solid by filtration. The solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with water, brine, and dried over MgSO4. The solvent was removed to give dark brown solid which was purified by chromatography on silica gel. Elution with Hexane:acetone mixture (80:20) gave the final compound as a tan solid. MS m/z: 201.3 (M+H). Calc""d. for C11H8N2O2xe2x88x92200.23.
Preparation BS: 3-(3-Aminophenyl)pyridine
To a pre-hydrogenated solution of Pd(OH)2 (298 mg, 2.12 mmol) in EtOH (10 mL) was added 3-(3-pyrid-1-yl)-1-nitrobenzene (440 mg, 2.12 mmol) in EtOH (10 mL). The resulting mixture was stirred at RT under H2 for 2 h. Solvent was separated from Pd(OH)2 by filtration through Celite(copyright). Solvent was then removed to give final compound as pale yellow solid. MS m/z: 171.3 (M+H). Calc""d. for C11H10N2xe2x80x94170.22.
Preparation BT: 2,2-Dimethyl-N-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-propionamide:
2,2,6,6-Tetramethylpiperidine (0.17 mL, 1.0 mmol) was added to a solution of N-pivaloyl-2-amino-6-bromomethylpyridine (180 mg, 0.66 mmol; M. Papadopoulou, et al., J. Het. Chem., 1995, 32, 675-681) in DMF (10 mL) at 25xc2x0 C. and the resulting mixture was stirred for 12 h. The reaction mixture was partitioned between H2O (15 mL) and EtOAc (20 mL) and the organics collected. The organics were washed with H2O (20 mL) followed by brine (20 mL) and dried over MgSO4. Concentration in vacuo gave a colorless oil. MS m/z: 330.1 (Mxe2x88x92H). Calc""d for C20H33N3Oxe2x80x94331.50.
Preparation BU: 6-(2,2,6,6-Tetramethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine:
KOH (1.68 g, 33.5 mmol) in MeOH (100 mL) was added to 2,2-dimethyl-N-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-propionamide (150 mg, 0.45 mmol) and the resulting mixture was heated at reflux for 12 h. After cooling to 25xc2x0 C., the mixture was neutralized to pH 7-8 with concentrated HCl and extracted with CHCl3 (3xc3x9775 mL). The organics were combined and dried over MgSO4. Concentration in vacuo gave a pale yellow solid. MS m/z: 247.7 (M+). Calc""d for C15H25N3xe2x80x94247.38.
Preparation BV: (2-Chloro-pyridin-4-yl)-piperidin-1-yl-methanone
To 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in dry CH2Cl2 (50 mL) was added piperidine (1.3 mL, 12.69 mmol), DIEA (2.2 mL, 12.69 mmol), HATU (1.2 g, 3.17 mmol), and EDCI (1.3 g, 6.98 mmol). The mixture was stirred under N2 at RT for 15 h. Solvent was removed and the crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (80:20) gave a white solid. MS m/z: 225.1 (M+H). Calc""d. for C11H13ClN2Oxe2x80x94224.07.
Preparation BW: (2-Amino-pyridin-4-yl)-piperidin-1-yl-methanone
NH4OH (25 mL) and Cu powder (100 mg) were added to a solution of (2-amino-pyridin-4-yl)-piperidin-1-yl-methanone (1.0 g, 4.45 mmol) in IpOH (15 mL) and the mixture was heated at 100xc2x0 C. for 48 h in a sealed tube. After cooling to RT, the mixture was partitioned between H2O and CHCl3. The aqueous layer was extracted with more CHCl3 (3xc3x9720 mL). The combined organic layers was washed with brine, and dried over MgSO4. Concentration in vacuo gave a light brown solid. MS m/z: 206.3 (M+H). Calc""d. for C11H15N3Oxe2x80x94205.12.
Preparation BX: 4-Piperidin-1-ylmethyl-pyridin-2-ylamine
To a stirred solution of (2-amino-pyridin-4-yl)-piperidin-1-yl-methanone (100 mg, 0.487 mmol) in dry THF (10 mL) at 0xc2x0 C. was added LAH (1.5 mL, 1.46 mmol) dropwise. The mixture was heated to reflux for 20 h. The resulting mixture was cooled to 0xc2x0 C. and quenched with H2O (1.5 mL) dropwise followed by 10% NaOH (1.5 mL). Solvent was removed and the residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4. Concentration in vacuo gave a light brown liquid. MS m/z: 192.2 (M+H). Calc""d. for C11H17N3xe2x88x92191.14.
Preparation BY: 4-Diethylaminomethyl-pyridin-2-ylamine
Prepared in a manner similar to that described for 4-piperidin-1-ylmethyl-pyridin-2-ylamine. MS m/z: 180.2 (M+H). Calc""d. for CloH17N3xe2x80x94179.14.
Preparation BZ: [6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-carbamic Acid Tert-Butyl Ester
2,6-Dimethylpiperidine (0.24 mL, 1.74 mmol) was added to a solution of (6-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (250 mg, 0.87 mmol) in DMF (10 mL) followed by heating at 50xc2x0 C. and the resulting mixture was stirred for 18 h. The resulting mixture was partitioned between water (10 mL) and CHCl3 (20 mL). The organic layer was washed with H3O, brine, and dried over MgSO4. Concentration in vacuo gave a pale yellow solid. MS m/z: 320.3 (M+H). Calc""d. for C18H29N3O2xe2x80x94319.23.
Preparation CA: 6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine
HCl (1.25 mL, 1.25 mmol) in MeOH (15 mL) was added to [6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (200 mg, 0.63 mmol) followed by heating at 40xc2x0 C. for 18 h. The resulting mixture was cooled to RT and basified to pH 9 with 2 N NaOH. The mixture was extracted with CHCl3 (3xc3x9720 mL). The combined organic layers was dried over MgSO4 and concentrated in vacuo to give a yellow oil. MS m/z: 220.2 (M+H). Calc""d. for C13H21N3xe2x80x94219.17.
Preparation CB: 1-(6-Bromo-pyridin-2-yl)-ethanol
6-Bromo-2-pyridine carboxaldehyde (1.0 g, 5.37 mmol) in dry THF (20 mL) was cooled to xe2x88x9278xc2x0 C. followed by adding MeMgI (2.0 mL, 5.91 mmol) dropwise via the addition funnel. The cooling bath was removed. The resulting mixture was stirred for 1 h then quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between water and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4. Solvent was removed and crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (70:30) gave a white solid. MS m/z: 201.9(M+H). Calc""d. for C7H8BrNOxe2x80x94200.98.
Preparation CC: 1-(6-Bromo-pyridin-2-yl)-ethanone
Oxalyl chloride (2.1 mL, 3.81 mmol) in dry CH2Cl2 was cooled to xe2x88x9270xc2x0 C. followed by adding DMSO (0.6 mL, 8.39 mmol) dropwise. After stirred for 5 min under xe2x88x9260xc2x0 C., 1-(6-bromo-pyridin-2-yl)-ethanol (770 mg, 3.81 mmol) in dry CH2Cl2 (10 mL) was added dropwise. After stirred for 30 min, TEA (2.7 mL, 19.83 mmol) was added and the resulting mixture was warmed to RT and stirred for 1 h. The reaction mixture was quenched with H2O. The organic layer was washed with H2O, brine, and dried over MgSO4. Solvent was removed and the crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a white solid. MS m/z: 200.3(M+H). Calc""d. for C7H8BrNOxe2x80x94198.96.
Preparation CD: 2-Bromo-6-(1-piperidin-1-yl-ethyl)-pyridine
To a stirred solution of 1-(6-bromo-pyridin-2-yl)-ethanone (600 mg, 3.01 mmol) in dry CH2Cl2 (20 mL) was added piperidine (0.5 mL) followed by NaBH(OAc)3 (1.3 g, 12.06 mmol) and HOAc (0.7 mL, 6.03 mmol). The mixture was heated at 40xc2x0 C. for 72 h. The reaction was quenched with 2M Na2CO3 and stirred 1 h. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. This crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a light yellow solid. MS m/z: 269.2 (M+H). Calc""d. for C12H17BrN2xe2x80x94268.06.
Preparation CE: 2-Hydroxymethyl-piperidine-1-carboxylic Acid Tert-Butyl Ester
Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (50 g, 218.1 mmol) in dry THF (300 mL) was cooled to xe2x88x9278xc2x0 C. followed by adding BH3-THF solution (261.7 mL, 260.0 mmol) dropwise over 1 h. The resulting mixture was warmed to RT and stirred for 48 h. The reaction was quenched with HOAc/H2O (1:1 ratio, 100 mL). The resulting mixture was partitioned between EtOAc and sat. NaHCO3. The organic layer was washed with more sat. NaHCO3, H2O, brine, and dried over MgSO4. Concentration in vacuo gave a white solid. MS m/z: 216.2 (M+H). Calc""d. for C11H21NO3xe2x80x94215.15.
Preparation CF: 2-Formyl-piperidine-1-carboxylic Acid Tert-Butyl Ester
In a manner similar to that described in Preparation CC, 2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.32 mmol) was added to a mixture of oxalyl chloride (1.3 mL, 2.55 mmol) and DMSO (0.36 mL, 5.11 mmol) followed by adding TEA (1.7 mL, 12.07 mmol) to give a white solid. MS m/z: 214.2 (M+H). Calc""d. for C11H19NO3xe2x80x94213.14.
Preparation CG: 2-[(6-Amino-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic Acid Tert-Butyl Ester
In a manner similar to that described in Preparation CD, 2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69 mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) and stirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc""d. for C16H26N4O2xe2x80x94306.21.
Preparation CH: 5-Cyano-indole-1-carboxylic Acid Tert-Butyl Ester
To a solution of 5-cyanoindole (9.76 g, 68.7 mmol), 100 mL of anhydrous CH3CN, and DMAP (423 mg, 3.5 mmol) was added di-tert-butyl dicarbonate (15.78 g, 72.3 mmol). The resulting solution was stirred for 18 h then concentrated in vacuo. The resulting solid was redissolved in EtOAc (350 mL) and washed with 1N HCl (aq) (2xc3x9725 mL). The acidic aqueous solution was extracted with EtOAc (2xc3x97). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a light yellow solid. MS m/z: 243 (M+1). Calc""d for C14H14N2O2xe2x88x92242.47.
Preparation CI: 5-Thiocarbamoyl-indole-1-carboxylic Acid Tert-Butyl Ester
H2S (g) was bubbled through a solution of 5-cyano-indole-1-carboxylic acid tert-butyl ester (15.71 g, 64.8 mmol), 120 mL of pyridine, and TEA (27.5 mL, 197.3 mmol). The reaction was followed by LC-MS and concentrated in vacuo upon completion to give a black solid. MS m/z: 277 (M+1). Calc""d for C14H16N2O2S-276.36.
Preparation CJ: 5-(4-Ethoxycarbonyl-thiazol-2-yl)-indole-1-carboxylic Acid Tert-Butyl Ester
To a solution of 5-thiocarbamoyl-indole-1-carboxylic acid tert-butyl ester (13.16 g, 47.6 mmol) and 250 mL of EtOH was added ethyl bromopyruvate (6.05 mL, 48.2 mmol). The resulting solution was stirred at 60xc2x0 C. for 1.5 h, then concentrated in vacuo. The resulting solid was purified by flash chromatography on silica gel using 5% EtOAc/hexanexe2x86x9280% EtOAc/hexanexe2x86x92CH2Cl2 as the eluant to give a white solid. MS m/z: 373 (M+1). Calc""d for C19H20N2O4S-372.44.
Preparation CK: 5-(4-Carboxy-thiazol-2-yl)-indole-1-carboxylic Acid Tert-Butyl Ester
To a solution of 5-(4-ethoxycarbonyl-thiazol-2-yl)-indole-1-carboxylic acid tert-butyl ester (3.34 g, 9.0 mmol) and 125 mL of THF was added 1N NaOH (aq) (30.0 mL, 30.0 mmol). The solution was stirred for 24 h then concentrated in vacuo. The crude solid was redissolved in H2O and acidified with 5% KHSO4. The solid was filtered and dried in vacuo at 60xc2x0 C. to give a pinkish-white solid. MS m/z: 345 (M+1). Calc""d for C17H16N2O4S-344.39.
Preparation CL: 2-Bromo-thiazole-4-carboxylic Acid Ethyl Ester
To a stirred mixture of 2-amino-thiazole-4-carboxylic acid ethyl ester hydrobromide (10 g, 58 mmol), CuSO4 (26.9 g, 168 mmol) and NaBr (22.7 g, 221 mmol) in 9M H4SO4 (aq) (120 mL) at xe2x88x925xc2x0 C. xe2x88x920xc2x0 C., a pre-cooled solution of NaNO2 (4.4 g, 64 mmol) in H2O (40 mL) was added at such a rate to maintain the temperature at or below 0xc2x0 C. After complete addition the mixture was maintained at 0xc2x0 C. for another 30 min then warmed to RT over 2.5 h. The reaction mixture was diluted with H2O (120 mL) and extracted with Et2O (3xc3x97100 mL). The aqueous layer was separated, basified to pH 12 with 5N NaOH (aq), then extracted with Et2O (2xc3x97100 mL). The organic layers were combined, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:9, EtOAc:hexane) to yield the title compound as a white amorphous solid. MS m/z: 235.8, 237.8 (M+H). Calc""d. for C6H6BrNO2S-234.93.
Preparation CM: 2-Chloro-thiazole-4-carboxylic Acid Ethyl Ester
2-Amino-thiazole-4-carboxylic acid ethyl ester hydrobromide (34.46 g, 0.137 mol) was basified with a saturated solution of NaHCO3 (aq) (300 mL) and extracted with EtOAc (8xc3x97300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated in vacuo to liberate the free base. To a well stirred suspension of the free base in 9M H2SO4 (aq) (500 mL) at 00C to xe2x88x925xc2x0 C., CUSO4 (63.34 g, 0.397 mol) and NaCl (30.39 g, 0.520 mol) were added, followed by the dropwise addition of a solution of NaNO2 (10.39 g, 0.151 mol) in H2O (150 mL), over 45 min. The mixture was maintained at 0xc2x0 C. for 1 h then warmed to RT. After 1 h at RT the reaction mixture was diluted with H2O (2 L) and extracted with Et2O (3xc3x97300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated in vacuo to yield the title compound as a pale yellow amorphous solid (sufficiently pure to be used directly in the next step). MS m/z: 192.0 (M+H). Calc""d. for C6H6ClNO2S-191.64.
Preparation CN: 2-Chloro-thiazole-4-carboxylic Acid
To a stirred solution of 2-chlorothiazole-4-carboxylic acid ethyl ester (20.49 g, 0.107 mol) in THF (180 mL) at RT, a 1M solution of LiOH (aq) (160 mL, 0.160 mol) was added. The resulting solution was heated to 65xc2x0 C. for 1 h. The solvent was evaporated in vacuo. The residue was treated with brine (100 mL) and acidified to pH 1 with 1M HCl (aq). The precipitate was filtered off, washed with H2O (2xc3x9750 mL) and Et2O (2xc3x9750 mL) and dried in a vacuum oven at 60xc2x0 C. for 62 h to yield the title compound as a pale yellow solid. MS m/z: 164.1 (M+H). Calc""d. for C4H2ClNO2S-163.58.
Preparation CO: 2-Chloro-thiazole-4-carbonyl Azide
To a stirred solution of 2-chlorothiazole-4-carboxylic acid (15.30 g, 94 mmol) in anhydrous THF (200 mL) at 0xc2x0 C., under nitrogen, TEA (26.1 mL, 187 mmol) was added. After 30 min ethyl chloroformate (9.39 mL, 98 mmol) was added dropwise over 10 min. After 25 min a solution of NaN3 (6.38 g, 98 mmol) in H2O (110 mL) was added. The mixture was warmed to RT over 1 h then diluted with H2O (500 mL). The precipitate was filtered off and air dried to yield the title compound as a white amorphous solid. MS m/z: 189.3 (M+H). Calc""d. for C4HClN4OS-188.60.
Preparation CP: 2-Bromo-thiazole-4-carbonyl Azide
To a stirred solution of 2-bromo-thiazole-4-carboxylic acid (5.33 g, 25.7 mmol) in anhydrous THF (40 mL) at 0xc2x0 C., under N2, TEA (7.18 mL, 51.5 mmol) was added. After 30 min ethyl chloroformate (2.59 mL, 27.0 mmol) was added dropwise over 10 min. After 25 min a solution of NaN3 (1.76 g, 27.0 mmol) in H2O (12 mL) was added. The mixture was warmed to RT over 1 h then diluted with H2O (100 mL). The precipitate was filtered off and air dried to yield the title compound as a white amorphous solid. MS m/z: 233.2, 235.2 (M+H). Calc""d. for C4HBrN40S-233.05.
Preparation CQ: 3-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester
To a stirred solution of 3-(aminomethyl)-1-N-Boc-piperidine (1.64 g, 7.65 mmol) and TEA (1.6 mL, 11 mmol) in THF (5 mL) at 0xc2x0 C., benzyl chloroformate (1.15 mL, 8.04 mmol) was added dropwise. The reaction was maintained at 0xc2x0 C. for 1 h, then warmed to RT overnight. The solvent was evaporated in vacuo. The residue was taken up in a saturated solution of NH4Cl (aq) (15 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:4, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 349.3 (M+H). Calc""d. for C19H28N2O4xe2x80x94348.44.
Preparation CR: Piperidin-3-ylmethyl-carbamic Acid Benzyl Ester
To a stirred solution of 3-(benxyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (983 mg, 2.82 mmol) in anhydrous CH2Cl2 (10 mL) at RT, under N2, TFA (3 mL) was added. After 2.5 h the solvent was evaporated in vacuo and the residue was dissolved in EtOAc (20 mL). The organic layer was washed with a saturated solution of NaHCO3 (aq) (30 mL), separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a pale yellow oil. MS m/z: 249.0 (M+H). Calc""d. for C19H28N2O4xe2x80x94248.32.
Preparation CS: 2-[3-(Benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylic Acid Ethyl Ester
To a stirred solution of piperidin-3-ylmethyl-carbamic acid benzyl ester (43 mg, 0.17 mmol) in CH3CN (5 mL), at RT under N2, K2CO3 (26 mg, 0.19 mmol) and 2-bromo-thiazole-4-carboxylic acid ethyl ester (41 mg, 0.17 mmol) were added. The resulting mixture was heated at reflux for 29 h. The solvent was evaporated in vacuo. The residue was treated with a saturated solution of NH4Cl (aq) (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:2, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 404.2 (M+H). Calc""d. for C20H25N3O4S-403.50.
Preparation CT: 2-[3-(Benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylic Acid
To a stirred solution of 2-[3-(benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylic acid ethyl ester (439 mg, 1.15 mmol) in THF (5 mL) at RT, a 1M solution of LiOH (aq) (1.72 mL, 1.72 mmol) was added. After 16 h the solvent was evaporated in vacuo. The residue was treated with brine (25 mL) and acidified to pH 1 with 2N HCl (aq) then extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a colorless oil. MS m/z: 355.9 (M+H). Calc""d. for C16H25N3O4S-355.45.
Preparation CU: Cyclopropanecarbothioamide
To a solution of cyclopropanecarboxamide (0.525 g, 6.169 mmol) and Na2CO3 (0.654 g, 6.169 mmol) in THF (100 mL) was added solid P2S5 (2.742 g, 6.169 mmol). The reaction was brought to reflux and kept at this temperature for 2 h. The reaction mixture was cooled to RT, filtered through Celite(copyright) and concentrated in vacuo to yield crude cyclopropane-carbothioamide (used for the next step without purification). MS m/z: 102.1 (M+H) Calc""d. for C4H8NSxe2x80x94102.0.
Preparation CV: Ethyl 2-cyclopropyl-thiazole-4-carboxylate
To a solution of cyclopropanecarbothiotic acid amide (1.18 g, 0.012 mol) in EtOH (60 mL) was added ethylbromopyruvate (1.71 mL, 0.012 mol) at RT and the mixture was brought to reflux and kept at this temperature for 3 h. The reaction mixture was cooled to RT and evaporated to dryness. Crude compound was dissolved in cold CH3CN (5 mL) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with hexanes:EtOAc (4:1) to give ethyl 2-cyclopropyl-thiazole-4-carboxylate. MS m/z: 197.9 (M+H) Calc""d. for C9Hl2NO2S-198.0.
Preparation CW: 2-Cyclopropyl-thiazole-4-carboxylic Acid
To a mixture of ethyl 2-cyclopropyl-thiazole-4-carboxylate (0.443 g, 2.249 mmol) and LiOH monohydrate (0.472 g, 11.243 mmol) was added a mixture of THF/MeOH/H2O (3:1:1, 50 mL). The reaction was stirred at RT for 24 h. The solution was acidified by addition of conc. HCl (0.1 mL) and the volatiles were removed. Remaining aqueous solution was extracted with EtOAc (3xc3x9720 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. MS m/z: 169.9 (M+H) Calc""d. for C7H7NO2S-170.0.
Preparation CX: 2-Cyclopropyl-thiazole-4-carbonyl Azide
To a solution of 2-cyclopropyl-thiazole-4-carboxylic acid (0.360 g, 2.130 mmol) and TEA (0.59 mL, 4.260 mmol) in THF (10 mL) at 0xc2x0 C., was added ethylchloroformate (0.22 mL, 2.343 mmol) and the mixture was stirred for 30 min. A solution of NaN3 (0.152 g, 2.343 mmol) in H2O (10 mL) was added to this mixture and warmed to RT. After 1 h, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3xc3x9720 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness. MS m/z: 195.0 (M+H) Calc""d. for C7H7N4OS-195.0.
Preparation CY: 2-tert-Butyl-thiazole-4-carbonylazide
Synthesized from 2,2-dimethylpropionamide following preparations CU-CX. MS m/z: 211.3 (M+H) Calc""d. for C8H11N4OS-211.0.
Preparation CZ: 3-Sulfamoylthiobenzamide
3-Cyanobenzenesulfonamide (12.6 g, 0.067 mol) was added to a solution of TEA (0.8 mL), dry pyridine (0.5 mL) and benzene (30 mL) at RT and cooled to 0xc2x0 C. H2S was bubbled through the solution for 20 min. The reaction was stirred at RT for 20 h. The resulting solid was dissolved in MeOH (30 mL) and transferred for the next step. LC-MS m/z: 217 (M+H).
Preparation DA: 2-(3-Sulfamoyl-phenyl)-thiazole-4-carbonylazide
Synthesized from 3-sulfamoylthiobenzamide following preparations CV-CX. MS m/z: 310.2 (M+H). Calc""d. for C10H8N5O3S2xe2x80x94310.0.
Preparation DB: Ethyl 2-cyclopropylethynyl-thiazole-4-carboxylate
To a solution of bromothiazole (319.5 mg, 1.353 mmol), Pd(PhCN)2Cl2 (155.7 mg, 0.406 mmol), CuI2 (51.5 mg, 0.271 mmol) and tri-t-butylphosphine (0.2 M in toluene, 4.4 mL, 0.880 mmol) in dioxane (10 mL) was added DEA (0.21 mL, 2.030 mmol) and ethynylcyclopropane (107.2 mg, 1.624 mmol). The reaction mixture was stirred at RT for 12 h. Volatiles were removed in vacuo and was passed through a pad SiO2 (elution with EtOAc). Chromatography (Hexanes: EtOAc, 9:1) gave pure ethyl 2-cyclopropylethynyl-thiazole-4-carboxylate. MS m/z: 222.2 (M+H) Calc""d. for C11H12NO2S-222.0.
Preparation DC: 2-Cyclopropylethynyl-thiazole-4-carbonyl Azide
Prepared from ethyl 2-cyclopropylethynyl-thiazole-4-carboxylate following preparations CW-CX. MS m/z: 219.3 (M+H) Calc""d. for C9H7N4OS-219.0.
Preparation DD: (6-Bromo-pyridin-2-ylmethyl)-isopropyl-amine
To a stirred solution of 6-bromo-pyridine-2-carbaldehyde (1.06 g, 5.73 nmmol) in dry CH2Cl2 (30 mL) was added isopropylamine (0.51 mL, 6.02 mmol). The mixture was stirred at RT and under N2 for 30 min followed by the addition of NaBH(OAc)3 (2.42 g, 11.46 mmol) and HOAc (1.3 mL, 22.92 mmol). The resulting cloudy light-yellow solution was stirred at RT and under N2 for 15 h. A 10% solution of Na2CO3 (50 mL) was added to the mixture and stirred for 30 min. The organic phase was separated, washed with H2O, brine, dried over MgSO4 and concentrated to afford a light yellow-oil without further purification. MS m/z: 229.1 (M+H). Calc""d for C9H13BrN2: 228.03.
Preparation DE: (6-Bromo-pyridin-2-ylmethyl)-isopropyl-carbamic Acid Tert-Butyl Ester
To a stirred solution of (6-bromo-pyridin-2-ylmethyl)-isopropyl-amine in CH2Cl2 (100 mL) was added (Boc)2O (10.2 g, 46.7 mmol). The resulting mixture was stirred at RT for 3 days. The mixture was concentrated and purified by chromatography on silica gel using 6:1 Hex/EtOAc as eluent to afford a very pale yellow-oil which solidified once cooled to RT. MS m/z: 329.3 (M+H). Calc""d for C14H21BrN2O2: 328.08.
Preparation DF: 4-pyrrolidin-1-ylmethylphenol
To a stirred solution of 4-hydroxylbenzaldehyde (10 g, 81.9 mmol) in anhydrous CH2Cl2 (500 mL) at RT, under N2, pyrrolidine (10.2 mL, 122.9 mmol) was added, followed by NaBH(OAc)3 (34.6 g, 163.9 mmol) and AcOH (19.7 g, 327.8 mmol). After the mixture was stirred at RT for 24 h, a saturated solution of NaHCO3(aq) (150 mL) was added. The mixture was vigorously stirred for an additional 1 h and then extracted with CH2Cl2 (3xc3x97200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as amber oil. This was used crude in the next step. MS m/z: 178 (M+1). Calc""d for C11H15NOxe2x80x94177.2.
Preparation DG: 2-Bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine
To a stirred suspension of NaH (2.6 g, 108.5 mmol) in DMF (300 mL) at 0xc2x0 C., under N2, a solution of 4-pyrrolidin-1-ylmethylphenol (16 g, 90.4 mmol) was added slowly. After stirring at 0xc2x0 C. for 30 min, 2,6-dibromopyridine (23.6 g, 99.4 mmol) was added and the resulting mixture was heated at 950C for 20 h. After cooling to RT, 200 mL of H2O was added and the mixture was extracted with EtOAc (3xc3x97300 mL). The combined organic layer was washed with brine (3xc3x97400 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an amber solid. This was used crude in the next step. MS m/z: 333 (M+1). Calc""d for C16H17BrN2O-333.2
Preparation DH: 2-Amino-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine
A mixture of 2-bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine (20 g) and Cu powder (1 g) in concentrated NH4OH (250 mL, aq) and IpOH (60 mL) was heated at 100xc2x0 C. in a sealed flask for 48 h. After cooling to RT, brine (300 mL) was added and the mixture was extracted with EtOAc (3xc3x97200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residues were filtered through silica gel pad eluting with MeOH/CH2Cl2 (5%). The filtrate was concentrated to dryness, then 50 mL of MeOH was added. After stirring for a while the solid was filtered to give the title compound. MS m/z: 270 (M+1). Calc""d for C16H19N3Oxe2x80x94269.3.
Preparation DI: 5-tert-Butyl-oxazole-2-carboxylic Acid Ethyl Ester
The mixture of N-(3,3-dimethyl-2-oxo-butyl)-oxalamic acid ethyl ester (0.79 g, 3.67 mmol) and phosphorus oxychloride (2.0 mL, 22.0 mmol) was stirred at 105xc2x0 C. under N2 for 2 h, cooled to RT, quenched slowly with ice-water, extracted with EtOAc. The combined organic portions were washed with brine, dried with Na2SO4, removal of the solvents gave a dark brownish oil which was purified by flash column chromatography to yield the title compound. MS m/z: 197.9 (M+H). Calc""d for C10H15NO3xe2x80x94197.23.
Preparation DJ: 5-tert-Butyl-oxazole-2-carboxylic Acid Amide
The mixture of 5-tert-butyl-oxazole-2-carboxylic acid ethyl ester(0.52 g, 2.64 nmmol) and NH3 (2.0M solution in MeOH, 6.6 mL, 13.2 mmol) was stirred at RT under N2 for 20 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc washed with brine, dried with Na2SO4 and filtered. Removal of the solvents afforded the title compound as a white solid. MS m/z: 169.2 (M+H). Calc""d for C8H12N2O2xe2x80x94168.19.
Preparation DK: 5-tert-Butyl-oxazole-2-carbothioic Acid Amide
In a manner similar to that described in preparation BB, the title compound was isolated as a yellow solid. MS m/z: 185.3 (M+H). Calc""d for C8H12N2OS-184.26.
Preparation DL: 2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carboxylic Acid Ethyl Ester
In a manner similar to that described in preparation BC, the title compound was isolated as a white solid. MS m/z: 281.2 (M+H). Calc""d for C13H16N2O3S-280.34.
Preparation DM: 2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carboxylic Acid
In a manner similar to that described in preparation BD, the title compound was isolated as a white solid. MS m/z: 253.3 (M+H). Calc""d for C12H12N2O3S-252.29.
Preparation DN: 2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carbonyl Azide
In a manner similar to that described in preparation BE, the title compound was isolated as an off-white solid. MS m/z: 278.2 (M+H)+. Calc""d for C11H11N5O2S-277.30.
Preparation DO: 2-Thiophen-2-yl-thiazole-4-carboxylic Acid Ethyl Ester
The mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (0.965 g, 4.09 mmol), 2-thiopheneboronic acid (0.52 g, 4.09 mmol), Pd(PPh3)4 (0.24 g, 0.20 mmol) in 6.2 mL of 2M Na2CO3 (aq) and 25 mL of ethylene glycol dimethyl ether was heated at reflux for 16 h, cooled to RT, diluted with H2O (25 mL), and extracted with EtOAc (30 mLxc3x973). The combined organic portions were washed with brine, dried with Na2SO4, and filtered. Removal of the solvents afforded a light yellowish oil which was purified by flash column chromatography (5% to 10% of EtOAc in hexanes). The desired compound was obtained as a pale solid. MS m/z: 239.9 (M+H). Calc""d for C10H9NO2S2xe2x80x94239.32.
Preparation DP: 2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carboxylic Acid Ethyl Ester
In a manner similar to that described in preparation BC, the title compound was isolated as a light yellowish viscous oil. MS m/z: 318.1 (M+H). Calc""d for C11H11NO4S3xe2x80x94317.41.
Preparation DQ: 2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carboxylic Acid
In a manner similar to that described in preparation BD, the title compound was isolated as a white solid. MS m/z: 290.0 (M+H). Calc""d for C9H7NO4S3xe2x80x94289.35.
Preparation DR: 2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carbonyl Azide
In a manner similar to that described in preparation BE, the title compound was isolated as a tan solid. MS m/z: 315.1 (M+H). Calc""d for C9H6N4O3S3xe2x80x94314.37.
Preparation DS: 6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-ylamine
In a manner similar to that described in Preparation EM, the title compound was isolated as a white solid. MS m/z: 208.1 (M+H). Calc""d for C11H17N3Oxe2x80x94207.27.
Preparation DT: 4-(6-Amino-pyridin-2-yloxymethyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester
In a manner similar to that described in Preparation EM, the title compound was isolated as a white solid. MS m/z: 308.2 (M+H). Calc""d for C16H25N3O3xe2x80x94307.39.
Preparation DU: D-2-Hydroxymethyl-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester
To a solution of D-prolinol (8 g, 79.2 mmol) and CH2Cl2 (150 mL) was added (Boc)2O (19 g, 87.1 mmol) and 150 mL of sat""d NaHCO3. The reaction was stirred at RT for 15 h. Extraction with CH2Cl2, washing with brine, drying (MgSO4) and concentration in vacuo gave D-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid. MS m/z: 202.3 (M+H). Calc""d for C10H19NO3xe2x80x94201.26.
Preparation DV: 2-(6-Bromo-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester
To a solution of D-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (15.9 g, 79.1 mmol) and dry DMF (250 mL) was added NaH (3.8 g, 94.9 mmol, 60% in mineral oil). Stirred at RT for 15 h, then added 2,6-dibromopyridine. Heated to 90xc2x0 C. for 2 h. Cooled and extracted with EtOAc. Washed organic layer with H2O and brine, dried (MgSO4) and concentrated in vacuo to give an orange oil. Purified by silica flash chromatography (10% EtOAc/hexane) to give the desired compound as a clear-colorless oil. MS m/z: 358.2 (M+H). Calc""d for C15H21BrN2O3xe2x80x94357.24.
Preparation DW: 2-(6-Amino-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester
In a manner similar to Preparation BW to give 2-(6-amino-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a viscous green oil. MS m/z: 294.3 (M+H). Calc""d for C15H23N3O3-293.36.
Preparation DX: 2-Bromo-6-(tetrahydro-furan-3-yloxy)-pyridine
To a solution of (S)-(+)-3-hydroxy-tetrahydrofuran (0.34 mL, 4.2 mmol) and dry THF (20 mL) was added NaH (0.17 g, 4.2 mmol, 60%) under N2 at RT. After 5 min, added 2,6-dibromopyridine. Stirred at RT for 4 h. Quenched with H2O and extracted with EtOAc. Washed organic layer with saturated NH4Cl, brine, dried (MgSO4) and concentrated in vacuo to give 2-bromo-6-(tetrahydro-furan-3-yloxy)-pyridine as a clear, colorless oil. MS m/z: 245.2 (M+H). Calc""d for C9H10BrNO2xe2x80x94244.09.
Preparation DY: 2-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine
In a manner similar to preparation DX from tetra-hydro-furfuryl alcohol to give 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine as a white solid. MS m/z: 259.2 (M+H). Calc""d for C10H12BrNO2 258.11.
Preparation DZ: 2-Bromo-6-(tetrahdyro-furan-2-ylmethoxy)-pyridine
In a manner similar to preparation DX from tetrahydro-3-furan methanol to give 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine as a white solid. MS m/z: 259.2 (M+H). Calc""d for C10H12BrNO2 258.11.
Preparation EA: 6-(Tetrahydro-furan-3-yloxy)-pyridin-2-ylamine
In a manner similar to preparation BW and 2-bromo-6-(tetrahydrofuran-3-yloxy)-pyridine to give 6-(tetrahydrofuran-3-yloxy)-pyridin-2-ylamine as a dark-green oil. MS m/z: 181.0 (M+H). Calc""d for C9H12N2O2-180.20.
Preparation EB: 6-(Tetrahydro-furan-2-ylmethoxy)-pyridin-2-ylamine
In a manner similar to preparation BW from 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine to give 6-(tetrahydro-furan-3-yloxy)-pyridin-2-ylamine as a dark-green oil. MS m/z: 384.3 (M+H). Calc""d for CloH14N2O2 194.23.
Preparation EC: 6-(Tetrahydro-furan-3-ylmethoxy)-pyridin-2-ylamine
In a manner similar to preparation BW from 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine to give 6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-ylamine as a yellow oil. MS m/z: 195.0 (M+H). Calc""d for C10H14N2O2 194.23.
Preparation ED: 6-Bromo-1xe2x80x2-methyl-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-1xe2x80x2H-[2,4xe2x80x2]bipyridinyl-4xe2x80x2-ol
To a solution of 1.07 M n-BuLi (36.4 mL) and dry THF (200 mL) chilled to xe2x88x9270xc2x0 C. under a blanket of N2 was added 2,6-dibromopyridine (10 g, 38.9 mmol)in 50 mL of dry THF slowly to maintain a temperature less than xe2x88x9269xc2x0 C. Stirred at xe2x88x9270xc2x0 C. for 20 min. Added 4-methylpiperidone (4.8 mL, 38.9 mmol) and stirred the mixture at xe2x88x9270xc2x0 C. for 1 h. Quenched with saturated NaHCO3 and extracted with EtOAc. Washed the organic layer with brine, dried (MgSO4) and concentrated in vacuo to give 6-bromo-1xe2x80x2-methyl-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-1xe2x80x2H-[2,4xe2x80x2]bipyridinyl-4xe2x80x2-ol as a light-yellow solid. MS m/z: 272.3 (M+H). Calc""d for C11H15BrN2O-271.15.
Preparation EE: 6-Bromo-1xe2x80x2-methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4%]bipyridinyl
To a 150 mL flask containing 6-bromo-1xe2x80x2-methyl-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-1xe2x80x2H-[2,4xe2x80x2]bipyridinyl-4xe2x80x2-ol (5 g, 18.5 mmol) was added conc. H2SO4 (50 mL). Heated to 100xc2x0 C. for 18 h. Cooled and poured onto ice carefully. Neutralized with 5 N NaOH and extracted with EtOAc. Washed with brine, dried (MgSO4) and concentrated in vacuo. Diluted residue with EtOAc and filtered. Concentrated filtrate in vacuo to give 6-bromo-1xe2x80x2-methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl as an orange oil. MS m/z: 254.2 (M+H). Calc""d for C11H13BrN2 253.14.
Preparation EF: 1xe2x80x2-Methyl-1xe2x80x2,2,3xe2x80x2,6xe2x80x2-tetrahdyro-[2,4xe2x80x2]bipyridinyl-6-ylamine
In a manner similar to preparation xxx from 6-bromo-1xe2x80x2-methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl to give 1xe2x80x2-methyl-1xe2x80x2,2,3xe2x80x2,6xe2x80x2-tetrahdyro-[2,4xe2x80x2]bipyridinyl-6-ylamine as a yellow oil. MS m/z: 190.0 (M+H). Calc""d for C11H15N3 189.26.
Preparation EG: 1xe2x80x2-Methyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-hexahydro-[2,4xe2x80x2]bipyridinyl-6-ylamine
A solution of lxe2x80x2-methyl-1xe2x80x2,2,3xe2x80x2,6xe2x80x2-tetrahdyro-[2,4xe2x80x2]bipyridinyl-6-ylamine (1.1 g, 5.8 mmol) and EtOH (30 mL) was hydrogenated over 20% Pd(OH)2/C (0.3 g)at 40 psi and RT. After 16 h, the mixture was filtered through Celite(copyright) and concentrated in vacuo to give the desired compound as a yellow solid. MS m/z: 192.1 (M+H). Calc""d for C11H17N3-191.27.
Preparation EH: 6-Bromo-4-hydroxy-3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic Acid Tert-Butyl Ester
In a manner similar to Preparation ED from N-Boc-piperidone to give the desired compound as a yellow oil. MS m/z: 358.0 (M+H). Calc""d for C15H21BrN2O3 357.24.
Preparation EI: 6-Bromo-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl
In a manner similar to Preparation EE from 6-bromo-4-hydroxy-3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic acid tert-butyl ester to give the desired compound as a yellow solid. MS m/z: 240.1 (M+H). Calc""d for C10H11BrN2 239.11.
Preparation EJ: 6-Bromo-3xe2x80x2,6xe2x80x2-dihydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic Acid Tert-Butyl Ester
To a solution of 6-bromo-1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-tetrahydro-[2,4xe2x80x2]bipyridinyl (4.3 g, 17.8 mmol)and CH2Cl2 (100 mL) was added saturated NaHCO3 (100 mL) and (Boc)2O (3.8 g, 17.8 mol). Stirred at RT for 18 h. Washed organic layer with brine then dried (MgSO4) and concentrated in vacuo to give the desired compound as a light-yellow oil. MS m/z: 338.9 (Mxe2x88x92H). Calc""d for C15HlgBrN2O2 339.23.
Preparation EK: 6-Amino-3xe2x80x2,4xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic Acid Tert-Butyl Ester
In a manner similar to Preparation EG from 6-amino-3xe2x80x2,6xe2x80x2-dihydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic acid tert-butyl ester to give the desired compound as a yellow oil. MS m/z: 278.3(M+H). Calc""d for C15H23N3O2 277.36.
Preparation EL: 6-Amino-3xe2x80x2,6xe2x80x2-dihydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic Acid Tert-Butyl Ester
In a manner similar to Preparation BW from 6-bromo-3xe2x80x2,6xe2x80x2-dihydro-2xe2x80x2H-[2,4xe2x80x2]bipyridinyl-1xe2x80x2-carboxylic acid tert-butyl ester to give the desired compound as a yellow oil. MS m/z: 275.6 (M+H). Calc""d for C15H21N3O2 275.35.
Preparation EM: 3-(6-Bromo-pyridin-2-ylamino)-propan-1-ol
A solution of 2,6-dibromopyridine (10 g, 42 mmol) and 3-aminopropanol (3.5 mL, 46 mmol) in THF (60 mL) was stirred at reflux for 48 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol as a light-yellow oil which crystallized on standing at RT to a white solid. MS m/z: 232.0 (M+H). Calc""d for C8H11BrN2O 231.09.
Preparation EN: (6-Bromo-pyridin-2-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine
A solution of 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol (4.2 g, 18 mmol), 3,4-dihydro-2H-pyran (1.6 mL, 18 mmol), TsOH (0.34 g, 1.8 mmol) and CH2Cl2 (100 mL) were stirred at RT. After 15 h, the reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a pale-yellow oil. MS m/z: 316.0 (M+H). Calc""d for C13H1gBrN2O2 315.21.
Preparation EO: N-[3-(Tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine
In a manner similar to Preparation BW from (6-bromo-pyridin-2-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine to give the desired compound as green oil. MS m/z: 252.0 (M+H). Calc""d for C13H21N3O2 251.32.
Preparation EP: 1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-[3-(tetrahydro-pyran-2-yloxy)-propylamino]-pyridin-2-yl]-urea
In a manner similar to Example 234, 2-(4-pyridinyl)-4-thiazolcarbonylazide and N-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine were heated together in toluene to give the desired compound as a yellow solid. MS m/z: 452.9 (Mxe2x88x92H). Calc""d for C22H26N6O3S 454.55.
Preparation EQ: 1-(2-Bromo-thiazol-4-yl)-3-(6-[3-(tetrahydro-pyran-2-yloxy)-propylamino]-pyridin-2-yl}-urea
In a manner similar to Example 234, 2-bromo-thiazole-4-carbonyl azide and N-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine were heated together in toluene to give the desired compound as a yellow solid. MS m/z: 457.3 (Mxe2x88x92H). Calc""d for C17H22BrN5O3S 456.36.
Preparation ER: 1-Acetyl-1H-indazole-5-carbonitrile
In a manner similar to that described by J. Sun, et al, J.O.C., 1997, p. 5627 from 4-amino-3-methylbenzo-nitrile, acetic anhydride, KOAc and CHCl3 to give 1-acetyl-1H-indazole-5-carbonitrile as a yellow solid. MS m/z: 186.0 (M+H). Calc""d for C10H7N3O 185.18.
Preparation ES: 1-Acetyl-1H-indazole-5-carbothioic Acid Amide
To a solution of 1-acetyl-1H-indazole-5-carbonitrile (1.1 g, 6 mmol), Et3N (2.5 mL, 17.8 mmol) and THF (20 mL) was bubbled in H2S gas over 10 min. Stirred at 0xc2x0 C. for 24 h. Concentrated in vacuo to give a yellow solid which was triturated with CH2Cl2 and filtered insoluble solid to give 1-acetyl-1H-indazole-5-carbothioic acid amide as a yellow solid. MS m/z: 220.0 (M+H). Calc""d for CloH9N3OS 219.26.
Preparation ET: 2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic Acid Ethyl Ester
In a manner similar to Preparation CV from 1-acetyl-1H-indazole-5-carbothioic acid amide to give 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester as a white solid. MS m/z: 316.2 (M+H). Calc""d for C15H13N3O3S 315.35.
Preparation EU: 2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic Acid
In a manner similar to Preparation CW from 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester to give 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid as a yellow solid following re-protection with Ac2O, Et3N, and THF. MS m/z: 286.1 (Mxe2x88x92H). Calc""d for C13H9N3O3S 287.29.
Preparation EV: 2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carbonyl azide
In a manner similar to Preparation CX from 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid to give 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carbonyl azide as a white solid. MS m/z: (M+H). Calc""d for C13H8N6O2S 312.31.
Preparation EW: 6-(1-Piperidin-1-yl-ethyl)-pyridin-2-ylamine
In a manner similar to that described in Preparation BW, 2-bromo-6-(1-piperidin-1-yl-ethyl)-pyridine (370 mg, 1.37 mmol) was heated with NH4OH (18 mL), IpOH (10 mL) and Cu (30 mg) in sealed tube to give a brown oil. MS m/z: 206.1 (M+H). Calc""d. for C12H19N3xe2x80x94205.16.
Preparation EX: (6-Amino-pyridin-2-ylmethyl)-isopropyl-carbamic Acid Tert-Butyl Ester
Prepared in a manner similar to preparation BW to give a pale yellow solid. EI-MS m/z 266.3 (M+H). Calc""d for C14H23N3O2: 265.18.